Triazolo-pyrazinyl derivatives useful as soluble guanylate cyclase activators

ABSTRACT

A compound of Formula I 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, are capable of modulating the body&#39;s production of cyclic guanosine monophosphate (“cGMP”) and are generally suitable for the therapy and prophylaxis of diseases which are associated with a disturbed cGMP balance. The invention furthermore relates to processes for preparing compounds of Formula I, or a pharmaceutically acceptable salt thereof, for their use in the therapy and prophylaxis of the abovementioned diseases and for preparing pharmaceuticals for this purpose, and to pharmaceutical compositions which comprise compounds of Formula I or a pharmaceutically acceptable salt thereof.

BACKGROUND OF THE INVENTION

Cyclic GMP (cGMP) is an important intracellular messenger which triggersa multitude of different effects via the modulation of cGMP-dependentprotein kinases, phosphodiesterases and ion channels. Examples are therelaxation of smooth muscles, the inhibition of thrombocyte activationand the inhibition of the proliferation of smooth-muscle cells and ofleukocyte adhesion. cGMP is produced by particulate and solubleguanylate cyclases as a response to a number of extracellular andintracellular stimuli. In the case of the particulate guanylatecyclases, stimulation is essentially effected by peptidic messengers,such as the atrial natriuretic peptide or the cerebral natriureticpeptide. The soluble guanylate cyclases (“sGC”), which are cytosolicheterodimeric heme proteins, in contrast, are essentially regulated by afamily of low-molecular-weight factors which are formed enzymatically.The most important stimulant is nitrogen monoxide (“NO”) or a closelyrelated species. The function of other factors such as carbon monoxideor the hydroxyl radical is still largely unclear. The binding of NO tothe heme with formation of a penta-coordinate heme-nitrosyl complex isproposed as the mechanism of the activation by NO. The associatedrelease of the histidine which is bound in the basal state to the ironconverts the enzyme into the active conformation.

Active soluble guanylate cyclases are each composed of an α and a βsubunit. Several subunit subtypes have been described which differ fromone another with respect to sequence, tissue-specific distribution andexpression in different development stages. The subtypes α₁ and β₁ aremainly expressed in brain and lung, while β₂ is found in particular inliver and kidney. The subtype α₂ was shown to be present in human fetalbrain. The subunits referred to as α₃ and β₃ were isolated from humanbrain and are homologous to α₁ and β₁. More recent works indicate anα_(2i) subunit which contains an insert in the catalytic domain. Allsubunits show great homologies in the region of the catalytic domain.The enzymes presumably contain one heme per heterodimer, which is boundvia β₁—Cys−78 and/or β₁-His-105 and is part of the regulatory center.

Under pathologic conditions, the formation ofguanylate-cyclase-activating factors can be reduced, or theirdegradation may be promoted owing to the increased occurrence of freeradicals. The resulting reduced activation of the sGC leads, via aweakening of the respective cGMP-mediated cellular response, for exampleto an increase of the blood pressure, to platelet activation or toincreased cell proliferation and cell adhesion. As a consequence,formation of endothelial dysfunction, atherosclerosis, hypertension,stable or unstable angina pectoris, thrombosis, myocardial infarction,strokes or erectile dysfunction results. Pharmacological stimulation ofsGC offers a possibility to normalize cGMP production and therefore maymake possible the treatment and/or prevention of such disorders.

For the pharmacological stimulation of the sGC, use has been made ofcompounds whose activity is based on an intermediate NO release, forexample organic nitrates. The drawback of this treatment is thedevelopment of tolerance and a reduction of activity, and the higherdosage which is required because of this.

Various sGC stimulators which do not act via NO release were describedby Vesely in a series of publications. However, the compounds, most ofwhich are hormones, plant hormones, vitamins or natural compounds suchas, for example, lizard poisons, predominantly only have weak effects onthe cGMP formation in cell lysates. D. L. Vesely, Eur. J. Clin. Invest.,vol. 15, 1985, p. 258; D. L. Vesely, Biochem. Biophys. Res. Comm., vol.88, 1979, p. 1244. A stimulation of heme-free guanylate cyclase byprotoporphyrin IX was demonstrated by Ignarro et al., Adv. Pharmacol.,vol. 26, 1994, p. 35. Pettibone et al., Eur. J. Pharmacol., vol. 116,1985 p. 307, described an antihypertensive action of diphenyliodoniumhexafluorophosphate and attributed this to a stimulation of sGC.According to Yu et al., Brit. J. Pharmacol, vol. 114, 1995, p. 1587,isoliquiritigenin, which has a relaxing action on isolated rat aortas,also activates sGC. Ko et al., Blood vol. 84, 1994, p. 4226, Yu et al.,Biochem. J. vol. 306, 1995, p. 787, and Wu et al., Brit. J. Pharmacol.vol. 116, 1995, p. 1973, demonstrated a sGC-stimulating activity of1-benzyl-3-(5-hydroxymethyl-2-furyl)indazole and demonstrated anantiproliferative and thrombocyte-inhibiting action. Pyrazoles and fusedpyrazoles which exhibit a sGC-stimulating activity are described inEuropean Patent No. 908,456 and German Patent Application No.19,744,027.

It has now been found that the compounds of the present invention effecta strong activation of soluble guanylate cyclase and are therefore maybe suitable for the therapy and prophylaxis of disorders which areassociated with a low cGMP level.

SUMMARY OF THE INVENTION

The present invention relates to compounds which activate solubleguanylate cyclase and are valuable pharmaceutically active compounds forthe therapy and prophylaxis of diseases, for example for cardiovasculardiseases such as hypertension, heart failure, pulmonary hypertension,angina pectoris, diabetes, cardiac insufficiency, thrombosis, chronickidney disease, fibrosis or atherosclerosis. The compounds of Formula I

are capable of modulating the body's production of cyclic guanosinemonophosphate (“cGMP”) and may be suitable for the therapy andprophylaxis of diseases which are associated with a disturbed cGMPbalance. The invention furthermore relates to processes for preparingcompounds of Formula I, to the use of such compounds for the therapy andprophylaxis of the above mentioned diseases and for preparingpharmaceuticals for this purpose, and to pharmaceutical compositionswhich comprise compounds of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds having structural FormulaI:

or a pharmaceutically acceptable salt thereof wherein:

-   C* indicates a potential chiral carbon atom;-   R¹ is    -   (1) hydrogen,    -   (2) (C₁₋₆)alkyl,    -   (3) halo(C₁₋₆)alkyl,    -   (4) (C₁₋₆)alkyl-O—,    -   (5) halo(C₁₋₆)alkyl-O—,    -   (6) (C₁₋₆)alkyl-NH—,    -   (7) halo(C₁₋₆)alkyl-NH—,    -   (8) —(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl,    -   (9) —(C₁₋₃)alkyl-aryl, wherein aryl is unsubstituted or        substituted by one, two, or three R⁷,    -   (10) aryl unsubstituted or substituted by one, two, or three R⁷,    -   (11) (C₃₋₇)cycloalkyl, or    -   (12) —(C₁₋₃)alkyl-heteroaryl wherein the heteroaryl is a 5- or        6-membered ring containing one, two, or three heteroatoms        independently selected from the group consisting of N, O, and S,        wherein heteroaryl is unsubstituted or substituted by one, two,        or three R⁷;-   R² is    -   (1) (C₁₋₃)alkyl, or    -   (2) (C₃₋₇)cycloalkyl;-   R³ is    -   (1) aryl unsubstituted or substituted by one, two, or three R⁶,    -   (2) five- or six-membered heteroaryl containing one, two or        three heteroatoms independently selected from the group        consisting of N, O and S, wherein heteroaryl is unsubstituted or        substituted one, two, or three R⁶,    -   (3) (C₁₋₃)alkyl, or    -   (4) (C₃₋₇)cycloalkyl;-   R⁴ is    -   (1) hydrogen,    -   (2) (C₁₋₃)alkyl,    -   (3) halo(C₁₋₃)alkyl, or    -   (4) (C₃₋₇)cycloalkyl;-   R⁵ is    -   (1) hydrogen,    -   (2) hydroxy,    -   (3) —N(R^(8a))(R^(8b)),    -   (4) —COOH,    -   (5) —C(O)NH₂,    -   (6) (C₁₋₃)alkyl,    -   (7) (C₃₋₇)cycloalkyl, or    -   (8) four- to six-membered monocyclic heterocyclyl containing 1 N        hetero atom, wherein the heterocyclyl is unsubstituted or        substituted by one to two R⁹;-   each R⁶ is independently    -   (1) (C₁₋₃)alkyl,    -   (2) halo(C₁₋₃)alkyl,    -   (3) (C₁₋₃)alkoxy,    -   (4) halo(C₁₋₃)alkoxy,    -   (5) (C₃₋₇)cycloalkyl, unsubstituted or substituted by halo,    -   (6) halo,    -   (7) cyano,    -   (8) hydroxy,    -   (9) —NH₂,    -   (10) —(C₁₋₆)alkyl—COOH, or    -   (11) —(C₁₋₆)alkyl-COO(C₁₋₄)alkyl;-   each R⁷ is independently    -   (1) (C₁₋₃)alkoxy,    -   (2) halo,    -   (3) hydroxy, or    -   (4) (C₁₋₃)alkyl;-   R^(8a) and R^(8b) are independently    -   (1) hydrogen,    -   (2) (C₁₋₃)alkyl, or    -   (3) (C₃₋₇)cycloalkyl; and-   R⁹ is    -   (1) (C₁₋₃)alkyl,    -   (2) halo(C₁₋₃)alkyl, or    -   (3) hydroxy.

In one embodiment, the present invention is directed to compounds havingstructural Formula I:

or a pharmaceutically acceptable salt thereof wherein:

-   C* indicates a potential chiral carbon atom;-   R¹ is    -   (1) hydrogen,    -   (2) (C₁₋₆)alkyl,    -   (3) halo(C₁₋₆)alkyl,    -   (4) (C₁₋₆)alkyl-O—,    -   (5) halo(C₁₋₆)alkyl-O—,    -   (6) (C₁₋₆)alkyl-NH—,    -   (7) halo(C₁₋₆)alkyl-NH—,    -   (8) —(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl,    -   (9) —(C₁₋₃)alkyl-aryl, wherein aryl is unsubstituted or        substituted by one, two, or three R⁷,    -   (10) aryl unsubstituted or substituted by one, two, or three R⁷,    -   (11) (C₃₋₇)cycloalkyl, or    -   (12) —(C₁₋₃)alkyl-heteroaryl wherein the heteroaryl is a 5- or        6-membered ring containing one, two, or three heteroatoms        independently selected from the group consisting of N, O, and S,        wherein heteroaryl is unsubstituted or substituted by one, two,        or three R⁷;-   R² is    -   (1) (C₁₋₃)alkyl, or    -   (2) (C₃₋₇)cycloalkyl;-   R³ is    -   (1) aryl unsubstituted or substituted by one, two, or three R⁶,        or    -   (2) five- or six-membered heteroaryl containing one, two or        three heteroatoms independently selected from the group        consisting of N, O and S, wherein heteroaryl is unsubstituted or        substituted one, two, or three R⁶;-   R⁴ is    -   (1) hydrogen,    -   (2) (C₁₋₃)alkyl,    -   (3) halo(C₁₋₃)alkyl, or    -   (4) (C₃₋₇)cycloalkyl;-   R⁵ is    -   (1) hydrogen,    -   (2) hydroxy,    -   (3) —N(R^(8a))(R^(8b)),    -   (4) —COOH,    -   (5) —C(O)NH₂,    -   (6) (C₁₋₃)alkyl,    -   (7) (C₃₋₇)cycloalkyl, or    -   (8) four- to six-membered monocyclic heterocyclyl containing 1 N        hetero atom, wherein the heterocyclyl is unsubstituted or        substituted by one to two R⁹;-   each R⁶ is independently    -   (1) (C₁₋₃)alkyl,    -   (2) halo(C₁₋₃)alkyl,    -   (3) (C₁₋₃)alkoxy,    -   (4) halo(C₁₋₃)alkoxy,    -   (5) (C₃₋₇)cycloalkyl, unsubstituted or substituted by halo,    -   (6) halo,    -   (7) cyano,    -   (8) hydroxy,    -   (9) —NH₂,    -   (10) —(C₁₋₆)alkyl—COOH, or    -   (11) —(C₁₋₆)alkyl-COO(C₁₋₄)alkyl;-   each R⁷ is independently    -   (1) (C₁₋₃)alkoxy,    -   (2) halo,    -   (3) hydroxy, or    -   (4) (C₁₋₃)alkyl;-   R^(8a) and R^(8b) are independently    -   (1) hydrogen,    -   (2) (C₁₋₃)alkyl, or    -   (3) (C₃₋₇)cycloalkyl; and-   R⁹ is    -   (1) (C₁₋₃)alkyl,    -   (2) halo(C₁₋₃)alkyl, or    -   (3) hydroxy.

In one embodiment, R¹ is hydrogen, (C₁₋₆)alkyl, halo(C₁₋₆)alkyl,(C₁₋₃)alkyl-aryl, wherein aryl is unsubstituted or substituted by one,two, or three R⁷; R² is (C₁₋₃)alkyl or (C₃₋₇)cycloalkyl; R³ is arylunsubstituted or substituted by one, two, or three R⁶, or five- orsix-membered heteroaryl containing one, two, or three heteroatomsindependently selected from the group consisting of N, O and S, whereinheteroaryl is unsubstituted or substituted one, two, or three R⁶; R⁴ ishydrogen or (C₁₋₃)alkyl; R⁵ is hydrogen, —NH₂, hydroxy, or C(O)NH₂; eachR⁶ (C₁₋₃)alkyl, halo(C₁₋₃)alkyl, (C₁₋₃)alkoxy, halo, hydroxy,(C₃₋₇)cycloalkyl, unsubstituted or substituted by halo or cyano; and R⁷is (C₁₋₃)alkoxy, halo, or hydroxy.

In one embodiment, R¹ is hydrogen, (C₁₋₆)alkyl, halo(C₁₋₆)alkyl, or—(C₁₋₃)alkyl-aryl, wherein aryl is unsubstituted or substituted by one,two, or three R⁷. In one embodiment, R¹ is (C₁₋₆)alkyl orhalo(C₁₋₆)alkyl.

In one embodiment, R¹ is (C₁₋₆)alkyl, halo(C₁₋₆)alkyl, or—(C₁₋₃)alkyl-aryl, wherein aryl is unsubstituted or substituted by one,two, or three R⁷.

In one embodiment, R¹ is hydrogen. In one class of this embodiment, R³is aryl unsubstituted or substituted by one, two, or three R⁶. In oneclass of this embodiment, R³ is five- or six-membered heteroarylcontaining one, two, or three heteroatoms independently selected fromthe group consisting of N, O and S, wherein heteroaryl is unsubstitutedor substituted by one, two, or three R⁶.

In one embodiment, R¹ is (C₁₋₆)alkyl. In one class of this embodiment,R³ is aryl unsubstituted or substituted by one, two, or three R⁶. In oneclass of this embodiment, R³ is five- or six-membered heteroarylcontaining one, two, or three heteroatoms independently selected fromthe group consisting of N, O and S, wherein heteroaryl is unsubstitutedor substituted by one, two, or three R⁶.

In one embodiment, R¹ is halo(C₁₋₆)alkyl. In one class of thisembodiment, R³ is aryl unsubstituted or substituted by one, two, orthree R⁶. In one class of this embodiment, R³ is five- or six-memberedheteroaryl containing one, two, or three heteroatoms independentlyselected from N, O and S, wherein heteroaryl is unsubstituted orsubstituted by one, two, or three R⁶.

In one embodiment, R¹ is (C₁₋₆)alkyl-O—. In one class of thisembodiment, R³ is aryl unsubstituted or substituted by one, two, orthree R⁶. In one class of this embodiment, R³ is five- or six-memberedheteroaryl containing one, two, or three heteroatoms independentlyselected from N, O and S, wherein heteroaryl is unsubstituted orsubstituted by one, two, or three R⁶.

In one embodiment, R¹ is halo(C₁₋₆)alkyl-O—. In one class of thisembodiment, R³ is aryl unsubstituted or substituted by one, two, orthree R⁶. In one class of this embodiment, R³ is five- or six-memberedheteroaryl containing one, two, or three heteroatoms independentlyselected from N, O and S, wherein heteroaryl is unsubstituted orsubstituted by one, two, or three R⁶.

In one embodiment, R¹ is (C₁₋₆)alkyl-NH—. In one class of thisembodiment, R³ is aryl unsubstituted or substituted by one, two, orthree R⁶. In one class of this embodiment, R³ is five- or six-memberedheteroaryl containing one, two, or three heteroatoms independentlyselected from N, O and S, wherein heteroaryl is unsubstituted orsubstituted by one, two, or three R⁶.

In one embodiment, R¹ is halo(C₁₋₆)alkyl-NH—. In one class of thisembodiment, R³ is aryl unsubstituted or substituted by one, two, orthree R⁶. In one class of this embodiment, R³ is five- or six-memberedheteroaryl containing one, two, or three heteroatoms independentlyselected from N, O and S, wherein heteroaryl is unsubstituted orsubstituted by one, two, or three R⁶.

In one embodiment, R¹ is —(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl. In one class ofthis embodiment, R³ is aryl unsubstituted or substituted by one, two, orthree R⁶. In one class of this embodiment, R³ is five- or six-memberedheteroaryl containing one, two, or three heteroatoms independentlyselected from N, O and S, wherein heteroaryl is unsubstituted orsubstituted by one, two, or three R⁶.

In one embodiment, R¹ is —(C₁₋₃)alkyl-aryl, wherein aryl isunsubstituted or substituted by one, two, or three R⁷. In one class ofthis embodiment, R³ is aryl unsubstituted or substituted by one, two, orthree R⁶. In one class of this embodiment, R³ is five- or six-memberedheteroaryl containing one, two, or three heteroatoms independentlyselected from N, O and S, wherein heteroaryl is unsubstituted orsubstituted by one, two, or three R⁶.

In one embodiment, R¹ is aryl unsubstituted or substituted by one, two,or three R⁷. In one class of this embodiment, R³ is aryl unsubstitutedor substituted by one, two, or three R⁶. In one class of thisembodiment, R³ is five- or six-membered heteroaryl containing one, two,or three heteroatoms independently selected from the group consisting ofN, O and S, wherein heteroaryl is unsubstituted or substituted by one,two, or three R⁶.

In one embodiment, R¹ is (C₃₋₇)cycloalkyl. In one class of thisembodiment, R³ is aryl unsubstituted or substituted by one, two, orthree R⁶. In one class of this embodiment, R³ is five- or six-memberedheteroaryl containing one, two, or three heteroatoms independentlyselected from N, O and S, wherein heteroaryl is unsubstituted orsubstituted by one, two, or three R⁶.

In one embodiment, R¹ is —(C₁₋₃)alkyl-heteroaryl wherein the heteroarylis a 5- or 6-membered ring containing one, two, or three heteroatomsindependently selected from N, O, and S, wherein heteroaryl isunsubstituted or substituted by one, two, or three R⁷. In one class ofthis embodiment, R³ is aryl unsubstituted or substituted by one, two, orthree R⁶. In one class of this embodiment, R³ is five- or six-memberedheteroaryl containing one, two, or three heteroatoms independentlyselected from the group consisting of N, O and S, wherein heteroaryl isunsubstituted or substituted by one, two, or three R⁶.

In one embodiment, R¹ is hydrogen,

In one class of this embodiment, R² is methyl or cyclopropyl.

In one subclass of this class, R³ is

In one sub-subclass of this subclass, R⁵ is hydroxy or —NH₂, hydrogen,or —C(O)NH₂.

In one sub-sub-subclass of this sub-subclass, R⁴ is hydrogen or methyl.

In one class of this embodiment, R¹ is

In one class of this embodiment, R¹ is

In one class of this embodiment, R¹ is

In one class of this embodiment, R¹ is

In one class of this embodiment, R¹ is

In one class of this embodiment, R¹ is

In one class of this embodiment, R¹ is

In one class of this embodiment, R¹ is

In one class of this embodiment, R¹ is

In one embodiment R² is (C₁₋₃)alkyl. In one class of this embodiment, R²is methyl.

In one embodiment R² is (C₃₋₇)cycloalkyl. In one class of thisembodiment, R² is cyclopropyl.

In one embodiment, R³ is

In one embodiment, R³ is aryl unsubstituted or substituted by one, two,or three R⁶.

In one class of this embodiment, R⁵ is N(R^(8a))(R^(8b)).

In one subclass of this class, R¹ is hydrogen. In one sub-subclass ofthis subclass, R² is (C₁₋₃)alkyl. In one sub-subclass of this subclass,R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₁₋₆)alkyl. In one sub-subclass ofthis subclass, R² is (C₁₋₃)alkyl. In one sub-subclass of this subclass,R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is halo(C₁₋₆)alkyl. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl. Inone sub-subclass of this subclass, R² is (C₁₋₃)alkyl. In onesub-subclass of this subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-aryl, wherein aryl isunsubstituted or substituted by one, two, or three R⁷. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is aryl unsubstituted or substitutedby one, two, or three R⁷. In one sub-subclass of this subclass, R² is(C₁₋₃)alkyl. In one sub-subclass of this subclass, R² is(C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₃₋₇)cycloalkyl. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-heteroaryl wherein theheteroaryl is a 5- or 6-membered ring containing one, two, or threeheteroatoms independently selected from N, O, and S, wherein heteroarylis unsubstituted or substituted by one, two, or three R⁷. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one class of this embodiment, R⁵ is hydroxy.

In one subclass of this class, R¹ is hydrogen. In one sub-subclass ofthis subclass, R² is (C₁₋₃)alkyl. In one sub-subclass of this subclass,R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₁₋₆)alkyl. In one sub-subclass ofthis subclass, R² is (C₁₋₃)alkyl. In one sub-subclass of this subclass,R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is halo(C₁₋₆)alkyl. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl. Inone sub-subclass of this subclass, R² is (C₁₋₃)alkyl. In onesub-subclass of this subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-aryl, wherein aryl isunsubstituted or substituted R⁷. In one sub-subclass of this subclass,R² is (C₁₋₃)alkyl. In one sub-subclass of this subclass, R² is(C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is aryl unsubstituted or substitutedby one, two, or three R⁷. In one sub-subclass of this subclass, R² is(C₁₋₃)alkyl. In one sub-subclass of this subclass, R² is(C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₃₋₇)cycloalkyl. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₁₋₃)alkyl-heteroaryl wherein theheteroaryl is a 5- or 6-membered ring containing one, two, or threeheteroatoms independently selected from N, O, and S, wherein heteroarylis unsubstituted or substituted by one, two, or three R⁷. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one class of this embodiment, R⁵ is hydrogen.

In one subclass of this class, R¹ is hydrogen. In one sub-subclass ofthis subclass, R² is (C₁₋₃)alkyl. In one sub-subclass of this subclass,R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₁₋₆)alkyl. In one sub-subclass ofthis subclass, R² is (C₁₋₃)alkyl. In one sub-subclass of this subclass,R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is halo(C₁₋₆)alkyl. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl. Inone sub-subclass of this subclass, R² is (C₁₋₃)alkyl. In onesub-subclass of this subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-aryl, wherein aryl isunsubstituted or substituted by one, two, or three R⁷. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is aryl unsubstituted or substitutedby one, two, or three R⁷. In one sub-subclass of this subclass, R² is(C₁₋₃)alkyl. In one sub-subclass of this subclass, R² is(C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₃₋₇)cycloalkyl. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-heteroaryl wherein theheteroaryl is a 5- or 6-membered ring containing one, two, or threeheteroatoms independently selected from N, O, and S, wherein heteroarylis unsubstituted or substituted by one, two, or three R⁷. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one class of this embodiment, R⁵ is COOH or —C(O)NH₂.

In one subclass of this class, R¹ is hydrogen. In one sub-subclass ofthis subclass, R² is (C₁₋₃)alkyl. In one sub-subclass of this subclass,R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₁₋₆)alkyl. In one sub-subclass ofthis subclass, R² is (C₁₋₃)alkyl. In one sub-subclass of this subclass,R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is halo(C₁₋₆)alkyl. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl. Inone sub-subclass of this subclass, R² is (C₁₋₃)alkyl. In onesub-subclass of this subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-aryl, wherein aryl isunsubstituted or substituted by one, two, or three R⁷. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is aryl unsubstituted or substitutedby one, two, or three R⁷. In one sub-subclass of this subclass, R² is(C₁₋₃)alkyl. In one sub-subclass of this subclass, R² is(C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₃₋₇)cycloalkyl. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-heteroaryl wherein theheteroaryl is a 5- or 6-membered ring containing one, two, or threeheteroatoms independently selected from N, O, and S, wherein heteroarylis unsubstituted or substituted by one, two, or three R⁷. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one class of this embodiment, R⁵ is (C₁₋₃)alkyl.

In one subclass of this class, R¹ is hydrogen. In one sub-subclass ofthis subclass, R² is (C₁₋₃)alkyl. In one sub-subclass of this subclass,R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₁₋₆)alkyl. In one sub-subclass ofthis subclass, R² is (C₁₋₃)alkyl. In one sub-subclass of this subclass,R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is halo(C₁₋₆)alkyl. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl. Inone sub-subclass of this subclass, R² is (C₁₋₃)alkyl. In onesub-subclass of this subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-aryl, wherein aryl isunsubstituted or substituted by one, two, or three R⁷. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is aryl unsubstituted or substitutedby one, two, or three R⁷. In one sub-subclass of this subclass, R² is(C₁₋₃)alkyl. In one sub-subclass of this subclass, R² is(C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₃₋₇)cycloalkyl. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-heteroaryl wherein theheteroaryl is a 5- or 6-membered ring containing one, two, or threeheteroatoms independently selected from N, O, and S, wherein heteroarylis unsubstituted or substituted by one, two, or three R⁷. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one class of this embodiment, R⁵ is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is hydrogen. In one sub-subclass ofthis subclass, R² is (C₁₋₃)alkyl. In one sub-subclass of this subclass,R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₁₋₆)alkyl. In one sub-subclass ofthis subclass, R² is (C₁₋₃)alkyl. In one sub-subclass of this subclass,R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is halo(C₁₋₆)alkyl. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl. Inone sub-subclass of this subclass, R² is (C₁₋₃)alkyl. In onesub-subclass of this subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-aryl, wherein aryl isunsubstituted or substituted by one, two, or three R⁷. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is aryl unsubstituted or substitutedby one, two, or three R⁷. In one sub-subclass of this subclass, R² is(C₁₋₃)alkyl. In one sub-subclass of this subclass, R² is(C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₃₋₇)cycloalkyl. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₁₋₃)alkyl-heteroaryl wherein theheteroaryl is a 5- or 6-membered ring containing one, two, or threeheteroatoms independently selected from the group consisting of N, O,and S, wherein heteroaryl is unsubstituted or substituted by one, two,or three R⁷. In one sub-subclass of this subclass, R² is (C₁₋₃)alkyl. Inone sub-subclass of this subclass, R² is (C₃₋₇)cycloalkyl.

In one class of this embodiment, R⁵ is four- or six-membered monocyclicheterocyclyl containing 1 N heteroatom, wherein the heterocyclyl isunsubstituted or substituted by one to two R⁹.

In one subclass of this class, R¹ is hydrogen. In one sub-subclass ofthis subclass, R² is (C₁₋₃)alkyl. In one sub-subclass of this subclass,R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₁₋₆)alkyl. In one sub-subclass ofthis subclass, R² is (C₁₋₃)alkyl. In one sub-subclass of this subclass,R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is halo(C₁₋₆)alkyl. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl. Inone sub-subclass of this subclass, R² is (C₁₋₃)alkyl. In onesub-subclass of this subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-aryl, wherein aryl isunsubstituted or substituted by one, two, or three R⁷. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is aryl unsubstituted or substitutedby one, two, or three R⁷. In one sub-subclass of this subclass, R² is(C₁₋₃)alkyl. In one sub-subclass of this subclass, R² is(C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₃₋₇)cycloalkyl. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-heteroaryl wherein theheteroaryl is a 5- or 6-membered ring containing one, two, or threeheteroatoms independently selected from N, O, and S heteroatoms, whereinheteroaryl is unsubstituted or substituted by one, two, or three R⁷. Inone sub-subclass of this subclass, R² is (C₁₋₃)alkyl. In onesub-subclass of this subclass, R² is (C₃₋₇)cycloalkyl.

In one embodiment, R³ is phenyl unsubstituted or substituted by one,two, or three R⁶.

In one class of this embodiment, R⁵ is —N(R^(8a))(R^(8b)).

In one subclass of this class, R¹ is hydrogen. In one sub-subclass ofthis subclass, R² is (C₁₋₃)alkyl. In one sub-subclass of this subclass,R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₁₋₆)alkyl. In one sub-subclass ofthis subclass, R² is (C₁₋₃)alkyl. In one sub-subclass of this subclass,R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is halo(C₁₋₆)alkyl. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl. Inone sub-subclass of this subclass, R² is (C₁₋₃)alkyl. In onesub-subclass of this subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-aryl, wherein aryl isunsubstituted or substituted by one, two, or three R⁷. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is aryl unsubstituted or substitutedby one, two, or three R⁷. In one sub-subclass of this subclass, R² is(C₁₋₃)alkyl. In one sub-subclass of this subclass, R² is(C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₃₋₇)cycloalkyl. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-heteroaryl wherein theheteroaryl is a 5- or 6-membered ring containing one, two, or threeheteroatoms independently selected from N, O, and S heteroatoms, whereinheteroaryl is unsubstituted or substituted by one, two, or three R⁷. Inone sub-subclass of this subclass, R² is (C₁₋₃)alkyl. In onesub-subclass of this subclass, R² is (C₃₋₇)cycloalkyl.

In one class of this embodiment, R⁵ is hydroxy.

In one subclass of this class, R¹ is hydrogen. In one sub-subclass ofthis subclass, R² is (C₁₋₃)alkyl. In one sub-subclass of this subclass,R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₁₋₆)alkyl. In one sub-subclass ofthis subclass, R² is (C₁₋₃)alkyl. In one sub-subclass of this subclass,R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is halo(C₁₋₆)alkyl. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl. Inone sub-subclass of this subclass, R² is (C₁₋₃)alkyl. In onesub-subclass of this subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₆)alkyl-aryl, wherein aryl isunsubstituted or substituted by one, two, or three R⁷. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is aryl unsubstituted or substitutedby one, two, or three R⁷. In one sub-subclass of this subclass, R² is(C₁₋₃)alkyl. In one sub-subclass of this subclass, R² is(C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₃₋₇)cycloalkyl. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₁₋₃)alkyl-heteroaryl wherein theheteroaryl is a 5- or 6-membered ring containing one, two, or threeheteroatoms independently selected from N, O, and S heteroatoms, whereinheteroaryl is unsubstituted or substituted by one, two, or three R⁷. Inone sub-subclass of this subclass, R² is (C₁₋₃)alkyl. In onesub-subclass of this subclass, R² is (C₃₋₇)cycloalkyl.

In one class of this embodiment, R⁵ is hydrogen.

In one subclass of this class, R¹ is hydrogen. In one sub-subclass ofthis subclass, R² is (C₁₋₃)alkyl. In one sub-subclass of this subclass,R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₁₋₆)alkyl. In one sub-subclass ofthis subclass, R² is (C₁₋₃)alkyl. In one sub-subclass of this subclass,R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is halo(C₁₋₆)alkyl. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl. Inone sub-subclass of this subclass, R² is (C₁₋₃)alkyl. In onesub-subclass of this subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-aryl, wherein aryl isunsubstituted or substituted by one, two, or three R⁷. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is aryl unsubstituted or substitutedby one, two, or three R⁷. In one sub-subclass of this subclass, R² is(C₁₋₃)alkyl. In one sub-subclass of this subclass, R² is(C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₃₋₇)cycloalkyl. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-heteroaryl wherein theheteroaryl is a 5- or 6-membered ring containing one, two, or threeheteroatoms independently selected from the group N, O, and S, whereinheteroaryl is unsubstituted or substituted by one, two, or three R⁷. Inone sub-subclass of this subclass, R² is (C₁₋₃)alkyl. In onesub-subclass of this subclass, R² is (C₃₋₇)cycloalkyl.

In one class of this embodiment, R⁵ is COOH or —C(O)NH₂.

In one subclass of this class, R¹ is hydrogen. In one sub-subclass ofthis subclass, R² is (C₁₋₃)alkyl. In one sub-subclass of this subclass,R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₁₋₆)alkyl. In one sub-subclass ofthis subclass, R² is (C₁₋₃)alkyl. In one sub-subclass of this subclass,R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is halo(C₁₋₆)alkyl. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl. Inone sub-subclass of this subclass, R² is (C₁₋₃)alkyl. In onesub-subclass of this subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-aryl, wherein aryl isunsubstituted or substituted by one, two, or three R⁷. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is aryl unsubstituted or substitutedby one, two, or three R⁷. In one sub-subclass of this subclass, R² is(C₁₋₃)alkyl. In one sub-subclass of this subclass, R² is(C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₃₋₇)cycloalkyl. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-heteroaryl wherein theheteroaryl is a 5- or 6-membered ring containing one, two, or threeheteroatoms independently selected from the group consisting of N, O,and S, wherein heteroaryl is unsubstituted or substituted by one, two,or three R⁷. In one sub-subclass of this subclass, R² is (C₁₋₃)alkyl. Inone sub-subclass of this subclass, R² is (C₃₋₇)cycloalkyl.

In one class of this embodiment, R⁵ is (C₁₋₃)alkyl.

In one subclass of this class, R¹ is hydrogen. In one sub-subclass ofthis subclass, R² is (C₁₋₃)alkyl. In one sub-subclass of this subclass,R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₁₋₆)alkyl. In one sub-subclass ofthis subclass, R² is (C₁₋₃)alkyl. In one sub-subclass of this subclass,R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is halo(C₁₋₆)alkyl. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl. Inone sub-subclass of this subclass, R² is (C₁₋₃)alkyl. In onesub-subclass of this subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-aryl, wherein aryl isunsubstituted or substituted by one, two, or three R⁷. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is aryl unsubstituted or substitutedby one, two, or three R⁷. In one sub-subclass of this subclass, R² is(C₁₋₃)alkyl. In one sub-subclass of this subclass, R² is(C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₃₋₇)cycloalkyl. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-heteroaryl wherein theheteroaryl is a 5- or 6-membered ring containing one, two, or threeheteroatoms independently selected from the group consisting of N, O,and S, wherein heteroaryl is unsubstituted or substituted by one, two,or three R⁷. In one sub-subclass of this subclass, R² is (C₁₋₃)alkyl. Inone sub-subclass of this subclass, R² is (C₃₋₇)cycloalkyl.

In one class of this embodiment, R⁵ is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is hydrogen. In one sub-subclass ofthis subclass, R² is (C₁₋₃)alkyl. In one sub-subclass of this subclass,R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₁₋₆)alkyl. In one sub-subclass ofthis subclass, R² is (C₁₋₃)alkyl. In one sub-subclass of this subclass,R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is halo(C₁₋₆)alkyl. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl. Inone sub-subclass of this subclass, R² is (C₁₋₃)alkyl. In onesub-subclass of this subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-aryl, wherein aryl isunsubstituted or substituted by one, two, or three R⁷. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is aryl unsubstituted or substitutedby one, two, or three R⁷. In one sub-subclass of this subclass, R² is(C₁₋₃)alkyl. In one sub-subclass of this subclass, R² is(C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₃₋₇)cycloalkyl. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₁₋₃)alkyl-heteroaryl wherein theheteroaryl is a 5- or 6-membered ring containing one, two, or threeheteroatoms independently selected from the group consisting of N, O,and S, wherein heteroaryl is unsubstituted or substituted by one, two,or three R⁷. In one sub-subclass of this subclass, R² is (C₁₋₃)alkyl. Inone sub-subclass of this subclass, R² is (C₃₋₇)cycloalkyl.

In one class of this embodiment, R⁵ is four- to six-membered monocyclicheterocyclyl containing 1 N heteroatom, wherein the heterocyclyl isunsubstituted or substituted by one to two R⁹.

In one subclass of this class, R¹ is hydrogen. In one sub-subclass ofthis subclass, R² is (C₁₋₃)alkyl. In one sub-subclass of this subclass,R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₁₋₆)alkyl. In one sub-subclass ofthis subclass, R² is (C₁₋₃)alkyl. In one sub-subclass of this subclass,R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is halo(C₁₋₆)alkyl. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl. Inone sub-subclass of this subclass, R² is (C₁₋₃)alkyl. In onesub-subclass of this subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-aryl, wherein aryl isunsubstituted or substituted by one, two, or three R⁷. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is aryl unsubstituted or substitutedby one, two, or three R⁷. In one sub-subclass of this subclass, R² is(C₁₋₃)alkyl. In one sub-subclass of this subclass, R² is(C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₃₋₇)cycloalkyl. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-heteroaryl wherein theheteroaryl is a 5- or 6-membered ring containing one, two, or threeheteroatoms independently selected from the group consisting of N, O,and S, wherein heteroaryl is unsubstituted or substituted by one, two,or three R⁷. In one sub-subclass of this subclass, R² is (C₁₋₃)alkyl. Inone sub-subclass of this subclass, R² is (C₃₋₇)cycloalkyl.

In one embodiment, R³ is five- or six-membered heteroaryl containingone, two, or three heteroatoms independently selected from the groupconsisting of N, O and S, wherein heteroaryl is unsubstituted orsubstituted by one, two, or three R⁶.

In one class of this embodiment, R⁵ is —N(R^(8a))(R^(8b)).

In one subclass of this class, R¹ is hydrogen. In one sub-subclass ofthis subclass, R² is (C₁₋₃)alkyl. In one sub-subclass of this subclass,R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₁₋₆)alkyl. In one sub-subclass ofthis subclass, R² is (C₁₋₃)alkyl. In one sub-subclass of this subclass,R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is halo(C₁₋₆)alkyl. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl. Inone sub-subclass of this subclass, R² is (C₁₋₃)alkyl. In onesub-subclass of this subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-aryl, wherein aryl isunsubstituted or substituted by one, two, or three R⁷. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is aryl unsubstituted or substitutedby one, two, or three R⁷. In one sub-subclass of this subclass, R² is(C₁₋₃)alkyl. In one sub-subclass of this subclass, R² is(C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₃₋₇)cycloalkyl. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-heteroaryl wherein theheteroaryl is a 5- or 6-membered ring containing one, two, or threeheteroatoms independently selected from the group consisting of N, O,and S, wherein heteroaryl is unsubstituted or substituted by one, two,or three R⁷. In one sub-subclass of this subclass, R² is (C₁₋₃)alkyl. Inone sub-subclass of this subclass, R² is (C₃₋₇)cycloalkyl.

In one class of this embodiment, R⁵ is hydroxy.

In one subclass of this class, R¹ is hydrogen. In one sub-subclass ofthis subclass, R² is (C₁₋₃)alkyl. In one sub-subclass of this subclass,R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₁₋₆)alkyl. In one sub-subclass ofthis subclass, R² is (C₁₋₃)alkyl. In one sub-subclass of this subclass,R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is halo(C₁₋₆)alkyl. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl. Inone sub-subclass of this subclass, R² is (C₁₋₃)alkyl. In onesub-subclass of this subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₁₋₃)alkyl-aryl, wherein aryl isunsubstituted or substituted by one, two, or three R⁷. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is aryl unsubstituted or substitutedby one, two, or three R⁷. In one sub-subclass of this subclass, R² is(C₁₋₃)alkyl. In one sub-subclass of this subclass, R² is(C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₃₋₇)cycloalkyl. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-heteroaryl wherein theheteroaryl is a 5- or 6-membered ring containing one, two, or threeheteroatoms independently selected from the group consisting of N, O,and S, wherein heteroaryl is unsubstituted or substituted by one, two,or three R⁷. In one sub-subclass of this subclass, R² is (C₁₋₃)alkyl. Inone sub-subclass of this subclass, R² is (C₃₋₇)cycloalkyl.

In one class of this embodiment, R⁵ is hydrogen.

In one subclass of this class, R¹ is hydrogen. In one sub-subclass ofthis subclass, R² is (C₁₋₃)alkyl. In one sub-subclass of this subclass,R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₁₋₆)alkyl. In one sub-subclass ofthis subclass, R² is (C₁₋₃)alkyl. In one sub-subclass of this subclass,R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is halo(C₁₋₆)alkyl. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl. Inone sub-subclass of this subclass, R² is (C₁₋₃)alkyl. In onesub-subclass of this subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-aryl, wherein aryl isunsubstituted or substituted by one, two, or three R⁷. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is aryl unsubstituted or substitutedby one, two, or three R⁷. In one sub-subclass of this subclass, R² is(C₁₋₃)alkyl. In one sub-subclass of this subclass, R² is(C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₃₋₇)cycloalkyl. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-heteroaryl wherein theheteroaryl is a 5- or 6-membered ring containing one, two, or threeheteroatoms independently selected from the group consisting of N, O,and S, wherein heteroaryl is unsubstituted or substituted by one, two,or three R⁷. In one sub-subclass of this subclass, R² is (C₁₋₃)alkyl. Inone sub-subclass of this subclass, R² is (C₃₋₇)cycloalkyl.

In one class of this embodiment, R⁵ is COOH or —C(O)NH₂.

In one subclass of this class, R¹ is hydrogen. In one sub-subclass ofthis subclass, R² is (C₁₋₃)alkyl. In one sub-subclass of this subclass,R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₁₋₆)alkyl. In one sub-subclass ofthis subclass, R² is (C₁₋₃)alkyl. In one sub-subclass of this subclass,R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is halo(C₁₋₆)alkyl. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl. Inone sub-subclass of this subclass, R² is (C₁₋₃)alkyl. In onesub-subclass of this subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-aryl, wherein aryl isunsubstituted or substituted by one, two, or three R⁷. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is aryl unsubstituted or substitutedby one, two, or three R⁷. In one sub-subclass of this subclass, R² is(C₁₋₃)alkyl. In one sub-subclass of this subclass, R² is(C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₃₋₇)cycloalkyl. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-heteroaryl wherein theheteroaryl is a 5- or 6-membered ring containing one, two, or threeheteroatoms independently selected from the group consisting of N, O,and S, wherein heteroaryl is unsubstituted or substituted by one, two,or three R⁷. In one sub-subclass of this subclass, R² is (C₁₋₃)alkyl. Inone sub-subclass of this subclass, R² is (C₃₋₇)cycloalkyl.

In one class of this embodiment, R⁵ is (C₁₋₃)alkyl.

In one subclass of this class, R¹ is hydrogen. In one sub-subclass ofthis subclass, R² is (C₁₋₃)alkyl. In one sub-subclass of this subclass,R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₁₋₆)alkyl. In one sub-subclass ofthis subclass, R² is (C₁₋₃)alkyl. In one sub-subclass of this subclass,R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is halo(C₁₋₆)alkyl. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl. Inone sub-subclass of this subclass, R² is (C₁₋₃)alkyl. In onesub-subclass of this subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-aryl, wherein aryl isunsubstituted or substituted by one, two, or three R⁷. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is aryl unsubstituted or substitutedby one, two, or three R⁷. In one sub-subclass of this subclass, R² is(C₁₋₃)alkyl. In one sub-subclass of this subclass, R² is(C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₃₋₇)cycloalkyl. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-heteroaryl wherein theheteroaryl is a 5- or 6-membered ring containing one, two, or threeheteroatoms independently selected from the group consisting of N, O,and S, wherein heteroaryl is unsubstituted or substituted by one, two,or three R⁷. In one sub-subclass of this subclass, R² is (C₁₋₃)alkyl. Inone sub-subclass of this subclass, R² is (C₃₋₇)cycloalkyl.

In one class of this embodiment, R⁵ is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is hydrogen. In one sub-subclass ofthis subclass, R² is (C₁₋₃)alkyl. In one sub-subclass of this subclass,R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₁₋₆)alkyl. In one sub-subclass ofthis subclass, R² is (C₁₋₃)alkyl. In one sub-subclass of this subclass,R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is halo(C₁₋₆)alkyl. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl. Inone sub-subclass of this subclass, R² is (C₁₋₃)alkyl. In onesub-subclass of this subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is —(C₁₋₃)alkyl-aryl, wherein aryl isunsubstituted or substituted by one, two, or three R⁷. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is aryl unsubstituted or substitutedby one, two, or three R⁷. In one sub-subclass of this subclass, R² is(C₁₋₃)alkyl. In one sub-subclass of this subclass, R² is(C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₃₋₇)cycloalkyl. In onesub-subclass of this subclass, R² is (C₁₋₃)alkyl. In one sub-subclass ofthis subclass, R² is (C₃₋₇)cycloalkyl.

In one subclass of this class, R¹ is (C₁₋₃)alkyl-heteroaryl wherein theheteroaryl is a 5- or 6-membered ring containing one, two, or threeheteroatoms independently selected from the group consisting of N, O,and S, wherein heteroaryl is unsubstituted or substituted by one, two,or three R⁷. In one sub-subclass of this subclass, R² is (C₁₋₃)alkyl. Inone sub-subclass of this subclass, R² is (C₃₋₇)cycloalkyl.

In one embodiment, R⁴ is (C₁₋₃)alkyl. In one class of this embodiment,R⁴ is methyl.

In one embodiment, R⁴ is halo(C₁₋₃)alkyl. In one embodiment, R⁴ ishydrogen. In one embodiment, R⁴ is (C₃₋₇)cycloalkyl.

In one embodiment, R⁵ is —N(R^(8a))(R^(8b)).

In one class of this embodiment, R² is (C₁₋₃)alkyl. In one subclass ofthis class, R⁴ is (C₁₋₃)alkyl. In one subclass of this class, R⁴ ishydrogen. In one subclass of this class, R⁴ is (C₃₋₇)cycloalkyl.

In one class of this embodiment, R² is (C₃₋₇)cycloalkyl. In one subclassof this class, R⁴ is (C₁₋₃)alkyl. In one subclass of this class, R⁴ ishydrogen. In one subclass of this class, R⁴ is (C₃₋₇)cycloalkyl.

In one embodiment, R⁵ is hydroxyl.

In one class of this embodiment, R² is (C₁₋₃)alkyl. In one subclass ofthis class, R⁴ is (C₁₋₃)alkyl. In one subclass of this class, R⁴ ishydrogen. In one subclass of this class, R⁴ is (C₃₋₇)cycloalkyl.

In one class of this embodiment, R² is (C₃₋₇)cycloalkyl. In one subclassof this class, R⁴ is (C₁₋₃)alkyl. In one subclass of this class, R⁴ ishydrogen. In one subclass of this class, R⁴ is (C₃₋₇)cycloalkyl.

In one embodiment, R⁵ is hydrogen.

In one class of this embodiment, R² is (C₁₋₃)alkyl. In one subclass ofthis class, R⁴ is (C₁₋₃)alkyl. In one subclass of this class, R⁴ ishydrogen. In one subclass of this class, R⁴ is (C₃₋₇)cycloalkyl.

In one class of this embodiment, R² is (C₃₋₇)cycloalkyl. In one subclassof this class, R⁴ is (C₁₋₃)alkyl. In one subclass of this class, R⁴ ishydrogen. In one subclass of this class, R⁴ is (C₃₋₇)cycloalkyl.

In one embodiment, R⁵ is COOH or —C(O)NH₂.

In one class of this embodiment, R² is (C₁₋₃)alkyl. In one subclass ofthis class, R⁴ is (C₁₋₃)alkyl. In one subclass of this class, R⁴ ishydrogen. In one subclass of this class, R⁴ is (C₃₋₇)cycloalkyl.

In one embodiment, R⁵ is (C₁₋₃)alkyl.

In one class of this embodiment, R² is (C₁₋₃)alkyl. In one subclass ofthis class, R⁴ is (C₁₋₃)alkyl. In one subclass of this class, R⁴ ishydrogen. In one subclass of this class, R⁴ is (C₃₋₇)cycloalkyl.

In one class of this embodiment, R² is (C₃₋₇)cycloalkyl. In one subclassof this class, R⁴ is (C₁₋₃)alkyl. In one subclass of this class, R⁴ ishydrogen. In one subclass of this class, R⁴ is (C₃₋₇)cycloalkyl.

In one embodiment, R⁵ is (C₃₋₇)cycloalkyl.

In one class of this embodiment, R² is (C₁₋₃)alkyl. In one subclass ofthis class, R⁴ is (C₁₋₃)alkyl. In one subclass of this class, R⁴ ishydrogen. In one subclass of this class, R⁴ is (C₃₋₇)cycloalkyl.

In one class of this embodiment, R² is (C₃₋₇)cycloalkyl. In one subclassof this class, R⁴ is (C₁₋₃)alkyl. In one subclass of this class, R⁴ ishydrogen. In one subclass of this class, R⁴ is (C₃₋₇)cycloalkyl.

In one embodiment, R⁵ is four- to six-membered monocyclic heterocyclylcontaining 1 N heteroatom, wherein the heterocyclyl is unsubstituted orsubstituted by one to two R⁹.

In one class of this embodiment, R² is (C₁₋₃)alkyl. In one subclass ofthis class, R⁴ is (C₁₋₃)alkyl. In one subclass of this class, R⁴ ishydrogen. In one subclass of this class, R⁴ is (C₃₋₇)cycloalkyl.

In one class of this embodiment, R² is (C₃₋₇)cycloalkyl. In one subclassof this class, R⁴ is (C₁₋₃)alkyl. In one subclass of this class, R⁴ ishydrogen. In one subclass of this class, R⁴ is (C₃₋₇)cycloalkyl.

In one embodiment, R⁶ is chloro, fluoro, hydroxy, trifluoromethyl,difluoromethyl, 1,1-difluoroethyl, cyano, methyl, isopropyl, methoxy,cyclopropyl, or fluoro-cyclopropyl.

In one embodiment, R⁷ is fluoro, hydroxy, or methoxy. In one embodiment,R⁷ is halo. In one class of this embodiment, R⁷ is fluoro. In oneembodiment, R⁷ is hydroxy. In one embodiment, R⁷ is (C₁₋₃)alkoxy. In oneclass of this embodiment, R⁷ is methoxy.

In one embodiment, R³ is phenyl, pyridinyl, triazolyl, pyrazinyl,pyrimidinyl, or oxadiazolyl, each unsubstituted or substituted by one,two, or three R⁶.

In one class of this embodiment, R² is methyl.

In one subclass of this class, R⁵ is hydroxy or —NH₂, hydrogen, or—C(O)NH₂. In one subclass of this class, R⁵ is hydroxy or —NH₂. In onesubclass of this class, R⁵ is hydroxy. In one subclass of this class, R⁵is —NH₂. In one subclass of this class, R⁵ is hydrogen. In one subclassof this class, R⁵ is —C(O)NH₂.

In one class of this embodiment, R² is cyclopropyl.

In one subclass of this class, R⁵ is hydroxy or —NH₂, hydrogen, or—C(O)NH₂. In one subclass of this class, R⁵ is hydroxy or —NH₂. In onesubclass of this class, R⁵ is hydroxy. In one subclass of this class, R⁵is —NH₂. In one subclass of this class, R⁵ is hydrogen. In one subclassof this class, R⁵ is —C(O)NH₂.

In one embodiment, R³ is phenyl unsubstituted or substituted by one,two, or three R⁶.

In one class of this embodiment, R² is methyl.

In one subclass of this class, R⁵ is hydroxy or —NH₂, hydrogen, or—C(O)NH₂. In one subclass of this class, R⁵ is hydroxy or —NH₂. In onesubclass of this class, R⁵ is hydroxy. In one subclass of this class, R⁵is —NH₂. In one subclass of this class, R⁵ is hydrogen. In one subclassof this class, R⁵ is —C(O)NH₂.

In one class of this embodiment, R² is cyclopropyl.

In one subclass of this class, R⁵ is hydroxy or —NH₂, hydrogen, or—C(O)NH₂. In one subclass of this class, R⁵ is hydroxy or —NH₂. In onesubclass of this class, R⁵ is hydroxy. In one subclass of this class, R⁵is —NH₂. In one subclass of this class, R⁵ is hydrogen. In one subclassof this class, R⁵ is —C(O)NH₂.

In one embodiment, R³ is pyridinyl unsubstituted or substituted by one,two, or three R⁶

In one class of this embodiment, R² is methyl.

In one subclass of this class, R⁵ is hydroxy or —NH₂, hydrogen, or—C(O)NH₂. In one subclass of this class, R⁵ is hydroxy or —NH₂. In onesubclass of this class, R⁵ is hydroxy. In one subclass of this class, R⁵is —NH₂. In one subclass of this class, R⁵ is hydrogen. In one subclassof this class, R⁵ is —C(O)NH₂.

In one class of this embodiment, R² is cyclopropyl.

In one subclass of this class, R⁵ is hydroxy or —NH₂, hydrogen, or—C(O)NH₂. In one subclass of this class, R⁵ is hydroxy or —NH₂. In onesubclass of this class, R⁵ is hydroxy. In one subclass of this class, R⁵is —NH₂. In one subclass of this class, R⁵ is hydrogen. In one subclassof this class, R⁵ is —C(O)NH₂.

In one embodiment, R³ is triazolyl unsubstituted or substituted by one,two, or three R⁶.

In one class of this embodiment, R² is methyl.

In one subclass of this class, R⁵ is hydroxy or —NH₂, hydrogen, or—C(O)NH₂. In one subclass of this class, R⁵ is hydroxy or —NH₂. In onesubclass of this class, R⁵ is hydroxy. In one subclass of this class, R⁵is —NH₂. In one subclass of this class, R⁵ is hydrogen. In one subclassof this class, R⁵ is —C(O)NH₂.

In one class of this embodiment, R² is cyclopropyl.

In one subclass of this class, R⁵ is hydroxy or —NH₂, hydrogen, or—C(O)NH₂. In one subclass of this class, R⁵ is hydroxy or —NH₂. In onesubclass of this class, R⁵ is hydroxy. In one subclass of this class, R⁵is —NH₂. In one subclass of this class, R⁵ is hydrogen. In one subclassof this class, R⁵ is —C(O)NH₂.

In one embodiment, R³ is pyrazinyl unsubstituted or substituted by one,two, or three R⁶.

In one class of this embodiment, R² is methyl.

In one subclass of this class, R⁵ is hydroxy or —NH₂, hydrogen, or—C(O)NH₂. In one subclass of this class, R⁵ is hydroxy or —NH₂. In onesubclass of this class, R⁵ is hydroxy. In one subclass of this class, R⁵is —NH₂. In one subclass of this class, R⁵ is hydrogen. In one subclassof this class, R⁵ is —C(O)NH₂.

In one class of this embodiment, R² is cyclopropyl.

In one subclass of this class, R⁵ is hydroxy or —NH₂, hydrogen, or—C(O)NH₂. In one subclass of this class, R⁵ is hydroxy or —NH₂. In onesubclass of this class, R⁵ is hydroxy. In one subclass of this class, R⁵is —NH₂. In one subclass of this class, R⁵ is hydrogen. In one subclassof this class, R⁵ is —C(O)NH₂.

In one embodiment, R³ is pyrimidinyl unsubstituted or substituted byone, two, or three R⁶.

In one class of this embodiment, R² is methyl.

In one subclass of this class, R⁵ is hydroxy or —NH₂, hydrogen, or—C(O)NH₂. In one subclass of this class, R⁵ is hydroxy or —NH₂. In onesubclass of this class, R⁵ is hydroxy. In one subclass of this class, R⁵is —NH₂. In one subclass of this class, R⁵ is hydrogen. In one subclassof this class, R⁵ is —C(O)NH₂.

In one class of this embodiment, R² is cyclopropyl.

In one subclass of this class, R⁵ is hydroxy or —NH₂, hydrogen, or—C(O)NH₂. In one subclass of this class, R⁵ is hydroxy or —NH₂. In onesubclass of this class, R⁵ is hydroxy. In one subclass of this class, R⁵is —NH₂. In one subclass of this class, R⁵ is hydrogen. In one subclassof this class, R⁵ is —C(O)NH₂.

In one embodiment, R³ is is oxadiazolyl unsubstituted or substituted byone, two, or three R⁶.

In one class of this embodiment, R² is methyl.

In one subclass of this class, R⁵ is hydroxy or —NH₂, hydrogen, or—C(O)NH₂. In one subclass of this class, R⁵ is hydroxy or —NH₂. In onesubclass of this class, R⁵ is hydroxy. In one subclass of this class, R⁵is —NH₂. In one subclass of this class, R⁵ is hydrogen. In one subclassof this class, R⁵ is —C(O)NH₂.

In one class of this embodiment, R² is cyclopropyl.

In one subclass of this class, R⁵ is hydroxy or —NH₂, hydrogen, or—C(O)NH₂. In one subclass of this class, R⁵ is hydroxy or —NH₂. In onesubclass of this class, R⁵ is hydroxy. In one subclass of this class, R⁵is —NH₂. In one subclass of this class, R⁵ is hydrogen. In one subclassof this class, R⁵ is —C(O)NH₂.

In one embodiment, R² is methyl or cycloalkyl. In one class of thisembodiment, R² is methyl. In one class of this embodiment, R² iscycloalkyl. In one subclass of this class, R² is cyclopropyl.

In one embodiment, the invention relates to compounds of Formula I-a:

or a pharmaceutically acceptable salt thereof, wherein k is 0 or 1;R^(10a) and R^(10b) are independently hydrogen or fluoro; and R², and R³are as previously defined.

In one embodiment, the invention relates to compounds of Formula I-b:

or a pharmaceutically acceptable salt thereof, wherein k is 0 or 1;R^(10a) and R^(10b) are independently hydrogen or fluoro; and R², R³, R⁴and R⁵ are as previously defined.

In one embodiment, the invention relates to compounds of Formula I-c:

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, or3; and R², R³, and R⁷ are as previously defined.

In one embodiment, the invention relates to compounds of Formula I-d:

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, or3; and R², R³, and R⁷ are as previously defined.

As will be apparent to those of skill in the art, compounds of FormulaI-b and I-d can exist in alternative tautomeric forms, with the ratiobetween the tautomeric forms varying depending on conditions. Forinstance, the tautomeric forms of the compound of Formula I-b are shownbelow.

The tautomeric forms of the compound of Formula I-d are shown below.

In one embodiment of this invention are compounds of Formula I, whereinthe compounds exist as S and R enantiomers with respect to C*. In oneclass of this embodiment, the compounds of Formula I exist as an Senantiomer with respect to C*. In one class of this embodiment, thecomponds of Formula I exist as R enantiomer with respect to C*.

In one embodiment of this invention includes the following compounds:

or a pharmaceutically acceptable salt thereof.

All structural Formulas, embodiments and classes thereof describedherein include the pharmaceutically acceptable salts of the compoundsdefined therein. Reference to the compounds of structural Formula Iincludes the compounds of other generic structural Formulas andembodiments that fall within the scope of Formula I, including but notlimited to Formula Ia to I-d.

“Alkyl”, as well as other groups having the prefix “alk”, such asalkoxy, and the like, means carbon chains which may be linear orbranched, or combinations thereof, containing the indicated number ofcarbon atoms. If no number is specified, 1-6 carbon atoms are intendedfor linear and 3-7 carbon atoms for branched alkyl groups. Examples ofalkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- andtert-butyl, pentyl, hexyl, heptyl, octyl, nonyl and the like.

“Alkoxy” and “alkyl-O—” are used interchangeably and refer to an alkylgroup linked to oxygen.

“Alkyl-NH—” refers to an alkyl group linked to an NH group. Examples ofalkyl-NH— include methyl-amino or methyl-NH— and ethyl-amino orethyl-NH—.

“Aryl” means phenyl or naphthyl.

“Haloalkyl” include mono-substituted as well as multiple halosubstituted alkyl groups, up to perhalo substituted alkyl. For example,halomethyl, 1,1-difluoroethyl, trifluoromethyl or1,1,1,2,2-pentafluorobutyl are included.

“Haloalkoxy” and “haloalkyl-O” are used interchangeably and refer tohalo substituted alkyl groups or “haloalkyl” linked through the oxygenatom. Haloalkoxy include mono-substituted as well as multiple halosubstituted alkoxy groups, up to perhalo substituted alkoxy. Forexample, trifluoromethoxy is included.

“Cycloalkyl” means a saturated cyclic hydrocarbon radical having thenumber of carbon atoms designated if no number of atoms is specified,3-7 carbon atoms are intended, forming 1-3 carbocyclic rings that arefused. “Cycloalkyl” also includes monocyclic rings fused to an arylgroup in which the point of attachment is on the non-aromatic portion.Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyland the like.

“Cycloalkoxy” and “cycloalkyl-O” are used interchangeably and refer to acycloalkyl group, as defined above, linked to oxygen.

“Heterocyclyl” “heterocycle” or “heterocyclic” refers to nonaromaticcyclic ring structures in which one or more atoms in the ring, theheteroatom(s), is an element other than carbon. Heteroatoms aretypically O, S or N atoms. Examples of heterocyclyl groups include:piperidine, piperazinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl,azetidinyl, oxiranyl, or aziridinyl, and the like.

“Heteroaryl” refers to an aromatic cyclic ring structures in which oneor more atoms in the ring, the heteroatom(s), is an element other thancarbon. Heteroatoms are typically O, S, or N atoms. Examples ofheteroaromatic groups include: pyridinyl, pyrimidinyl, pyrrolyl,pyridazinyl, isoxazolyl, indolyl, or imidazolyl.

“Halogen” (or “halo”) unless otherwise indicated, includes fluorine(fluoro), chlorine (chloro), bromine (bromo) and iodine (iodo). In oneembodiment, halo is fluoro (—F) or chloro (—Cl).

When any variable (e.g., R¹, R², etc.) occurs more than one time in anyconstituent or in Formula I or other generic formulas herein, itsdefinition on each occurrence is independent of its definition at everyother occurrence. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds. Inchoosing compounds of the present invention, one of ordinary skill inthe art will recognize that the various substituents, i.e., R¹, R²,etc., are to be chosen in conformity with well-known principles ofchemical structure connectivity and stability. Unless expressly statedto the contrary, substitution by a named substituent is permitted on anyatom in a ring (e.g., aryl, a heteroaryl ring, or a saturatedheterocyclic ring) provided such ring substitution is chemically allowedand results in a stable compound. A “stable” compound is a compoundwhich can be prepared and isolated and whose structure and propertiesremain or can be caused to remain essentially unchanged for a period oftime sufficient to allow use of the compound for the purposes describedherein (e.g., therapeutic or prophylactic administration to a subject).

The term “substituted” shall be deemed to include multiple degrees ofsubstitution by a named substituent. Where multiple substituent moietiesare disclosed or claimed, the substituted compound can be independentlysubstituted by one or more of the disclosed or claimed substituentmoieties, singly or plurally. By independently substituted, it is meantthat the (two or more) substituents can be the same or different.

Unless expressly depicted or described otherwise, variables depicted ina structural formula with a “floating” bond, such as R⁷ in Formulas I-cand I-d, are permitted on any available carbon atom in the ring to whichthe variable is attached. When a moiety is noted as being “optionallysubstituted” in Formulas I to Id or any embodiment thereof, it meansthat Formula I or the embodiment thereof encompasses compounds thatcontain the noted substituent (or substituents) on the moiety and alsocompounds that do not contain the noted substituent (or substituents) onthe moiety.

Compounds of structural Formulas I to I-d may contain one or moreasymmetric centers and can thus occur as racemates and racemic mixtures,single enantiomers, diastereoisomeric mixtures and individualdiastereoisomers. Centers of asymmetry that are present in the compoundsof Formula I can all independently of one another have S configurationor R configuration. The compounds of this invention include all possibleenantiomers and diastereomers and mixtures of two or more stereoisomers,for example mixtures of enantiomers and/or diastereomers, in all ratios.Thus, enantiomers are a subject of the invention in enantiomericallypure form, both as levorotatory and as dextrorotatory antipodes, in theform of racemates and in the form of mixtures of the two enantiomers inall ratios. In the case of a cis/trans isomerism the invention includesboth the cis form and the trans form as well as mixtures of these formsin all ratios. The present invention is meant to comprehend all suchstereo-isomeric forms of the compounds of structural Formulas I to I-d.

Compounds of structural Formulas I to I-d may be separated into theirindividual diastereoisomers by, for example, fractional crystallizationfrom a suitable solvent, for example methanol or ethyl acetate or amixture thereof, or via chiral chromatography using an optically activestationary phase. Absolute stereochemistry may be determined by X-raycrystallography of crystalline products or crystalline intermediateswhich are derivatized, if necessary, with a reagent containing anasymmetric center of known absolute configuration. Alternatively, anystereoisomer or isomers of a compound of Formulas I to I-d may beobtained by stereospecific synthesis using optically pure startingmaterials or reagents of known absolute configuration.

If desired, racemic mixtures of the compounds may be separated so thatthe individual enantiomers are isolated. The separation can be carriedout by methods well known in the art, such as the coupling of a racemicmixture of compounds to an enantiomerically pure compound to form adiastereoisomeric mixture, followed by separation of the individualdiastereoisomers by standard methods, such as fractional crystallizationor chromatography. The coupling reaction is often the formation of saltsusing an enantiomerically pure acid or base. The diasteromericderivatives may then be converted to the pure enantiomers by cleavage ofthe added chiral residue. The racemic mixture of the compounds can alsobe separated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.

For compounds of Formulas I to I-d described herein which containolefinic double bonds, unless specified otherwise, they are meant toinclude both E and Z geometric isomers.

Some of the compounds described herein may exist as tautomers which havedifferent points of attachment of hydrogen accompanied by one or moredouble bond shifts. For example, a ketone and its enol form areketo-enol tautomers. The individual tautomers as well as mixturesthereof are encompassed with compounds of Formulas I to I-d of thepresent invention.

In the compounds of structural Formulas I to I-d, the atoms may exhibittheir natural isotopic abundances, or one or more of the atoms may beartificially enriched in a particular isotope having the same atomicnumber, but an atomic mass or mass number different from the atomic massor mass number predominately found in nature. The present invention asdescribed and claimed herein is meant to include all suitable isotopicvariations of the compounds of structural Formulas I to I-d andembodiments thereof. For example, different isotopic forms of hydrogen(H) include protium (¹H) and deuterium (²H, also denoted herein as D).Protium is the predominant hydrogen isotope found in nature. Enrichingfor deuterium may afford certain therapeutic advantages, such asincreasing in vivo half-life or reducing dosage requirements, or mayprovide a compound useful as a standard for characterization ofbiological samples. Isotopically-enriched compounds within structuralFormulas I to I-d, can be prepared without undue experimentation byconventional techniques well known to those skilled in the art or byprocesses analogous to those described in the Schemes and Examplesherein using appropriate isotopically-enriched reagents and/orintermediates.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids. When thecompound of the present invention is acidic, its corresponding salt canbe conveniently prepared from pharmaceutically acceptable non-toxicbases, including inorganic bases and organic bases. Salts derived fromsuch inorganic bases include aluminum, ammonium, calcium, copper (ic andous), ferric, ferrous, lithium, magnesium, manganese (ic and ous),potassium, sodium, zinc and the like salts. Preferred are the ammonium,calcium, magnesium, potassium and sodium salts. Salts prepared frompharmaceutically acceptable organic non-toxic bases include salts ofprimary, secondary, and tertiary amines derived from both naturallyoccurring and synthetic sources. Pharmaceutically acceptable organicnon-toxic bases from which salts can be formed include, for example,arginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine,diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine,glucamine, glucosamine, histidine, hydrabamine, isopropylamine,dicyclohexylamine, lysine, methylglucamine, morpholine, piperazine,piperidine, polyamine resins, procaine, purines, theobromine,triethylamine, trimethylamine, tripropylamine, tromethamine and thelike. When the compound of the present invention is basic, itscorresponding salt can be conveniently prepared from pharmaceuticallyacceptable non-toxic inorganic and organic acids. Such acids include,for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,p-toluenesulfonic acid and the like. Preferred are citric, hydrobromic,hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids. If thecompounds of Formulas I to I-d simultaneously contain acidic and basicgroups in the molecule the invention also includes, in addition to thesalt forms mentioned, inner salts or betaines (zwitterions). Salts canbe obtained from the compounds of Formulas I to I-d by customary methodswhich are known to the person skilled in the art, for example bycombination with an organic or inorganic acid or base in a solvent ordispersant, or by anion exchange or cation exchange from other salts.The present invention also includes all salts of the compounds ofFormula I which, owing to low physiological compatibility, are notdirectly suitable for use in pharmaceuticals but which can be used, forexample, as intermediates for chemical reactions or for the preparationof pharmaceutically acceptable salts.

Furthermore, compounds of the present invention may exist in amorphousform and/or one or more crystalline forms, and as such all amorphous andcrystalline forms and mixtures thereof of the compounds of Formula I,including the Examples, are intended to be included within the scope ofthe present invention. In addition, some of the compounds of the instantinvention may form solvates with water (i.e., a hydrate) or commonorganic solvents such as but not limited to ethyl acetate. Such solvatesand hydrates, particularly the pharmaceutically acceptable solvates andhydrates, of the instant compounds are likewise encompassed within thescope of this invention, along with un-solvated and anhydrous forms.

Any pharmaceutically acceptable pro-drug modification of a compound ofthis invention which results in conversion in vivo to a compound withinthe scope of this invention is also within the scope of this invention.For example, esters can optionally be made by esterification of anavailable carboxylic acid (—COOH) group or by formation of an ester onan available hydroxy group in a compound. Similarly, labile amides canbe made. Pharmaceutically acceptable esters or amides of the compoundsof this invention may be prepared to act as pro-drugs which can behydrolyzed back to an acid (or —COO⁻ depending on the pH of the fluid ortissue where conversion takes place) or hydroxy form particularly invivo and as such are encompassed within the scope of this invention.Included are those esters and acyl groups known in the art for modifyingthe solubility or hydrolysis characteristics for use assustained-release or prodrug formulations. Also, in the case of acarboxylic acid (—COOH) or alcohol group being present in the compoundsof the present invention, pharmaceutically acceptable esters ofcarboxylic acid derivatives, such as methyl, ethyl, orpivaloyloxymethyl, or acyl derivatives of alcohols, such as O-acetyl,O-pivaloyl, O-benzoyl, and O-aminoacyl, can be employed.

The present invention also relates to processes for the preparation ofthe compounds of Formulas I to I-d which are described in the followingand by which the compounds of the invention are obtainable.

The compounds of Formulas I to I-d according to the invention effect anincrease of cGMP concentration via the activation of the solubleguanylate cyclase (sGC), and they therefore bay be useful agents for thetherapy and prophylaxis of disorders which are associated with a low ordecreased cGMP level or which are caused thereby, or for whose therapyor prophylaxis an increase of the present cGMP level is desired. Theactivation of the sGC by the compounds of Formulas I to I-d can beexamined, for example, in the activity assay described herein.

The terms “therapeutically effective (or efficacious) amount” andsimilar descriptions such as “an amount efficacious for treatment” areintended to mean that amount of a pharmaceutical drug that will elicitthe biological or medical response of a tissue, a system, animal orhuman that is being sought by a researcher, veterinarian, medical doctoror other clinician. The terms “prophylactically effective (orefficacious) amount” and similar descriptions such as “an amountefficacious for prevention” are intended to mean that amount of apharmaceutical drug that will prevent or reduce the risk of occurrenceof the biological or medical event that is sought to be prevented in atissue, a system, animal or human by a researcher, veterinarian, medicaldoctor or other clinician. As an example, the dosage a patient receivescan be selected so as to achieve the desired reduction in bloodpressure; the dosage a patient receives may also be titrated over timein order to reach a target blood pressure. The dosage regimen utilizinga compound of the instant invention is selected in accordance with avariety of factors including type, species, age, weight, sex and medicalcondition of the patient; the severity of the condition to be treated;the potency of the compound chosen to be administered; the route ofadministration; and the renal and hepatic function of the patient. Aconsideration of these factors is well within the purview of theordinarily skilled clinician for the purpose of determining thetherapeutically effective or prophylactically effective dosage amountneeded to prevent, counter, or arrest the progress of the condition. Itis understood that a specific daily dosage amount can simultaneously beboth a therapeutically effective amount, e.g., for treatment ofhypertension, and a prophylactically effective amount, e.g., forprevention of myocardial infarction.

Disorders and pathological conditions which are associated with a lowcGMP level or in which an increase of the cGMP level is desired and forwhose therapy and prophylaxis it is possible to use compounds ofFormulas I to I-d are, for example, cardiovascular diseases, such asendothelial dysfunction, diastolic dysfunction, atherosclerosis,hypertension, heart failure, pulmonary hypertension, which includespulmonary arterial hypertension (PAH), stable and unstable anginapectoris, thromboses, restenoses, myocardial infarction, strokes,cardiac insufficiency, fibrosis or pulmonary hypertonia, or, forexample, erectile dysfunction, asthma bronchiale, chronic kidneyinsufficiency and diabetes. Compounds of Formulas I to I-d canadditionally be used in the therapy of cirrhosis of the liver and alsofor improving a restricted memory performance or ability to learn.

The compounds of Formulas I to I-d and their pharmaceutically acceptablesalts can be administered to animals, preferably to mammals, and inparticular to humans, as pharmaceuticals by themselves, in mixtures withone another or in the form of pharmaceutical compositions. The term“patient” includes animals, preferably mammals and especially humans,who use the instant active agents for the prevention or treatment of amedical condition. Administering of the drug to the patient includesboth self-administration and administration to the patient by anotherperson. The patient may be in need of, or desire, treatment for anexisting disease or medical condition, or may be in need of or desireprophylactic treatment to prevent or reduce the risk of occurrence ofsaid disease or medical condition. As used herein, a patient “in need”of treatment of an existing condition or of prophylactic treatmentencompasses both a determination of need by a medical professional aswell as the desire of a patient for such treatment.

Subjects of the present invention therefore also are the compounds ofFormulas I to I-d and their pharmaceutically acceptable salts for use aspharmaceuticals, their use for activating soluble guanylate cyclase, fornormalizing a disturbed cGMP balance and in particular their use in thetherapy and prophylaxis of the above mentioned syndromes as well astheir use for preparing medicaments for these purposes.

Furthermore, a subject of the present invention is pharmaceuticalcompositions which comprise as active component an effective dose of atleast one compound of Formulas I to I-d and/or a pharmaceuticallyacceptable salt thereof and a customary pharmaceutically acceptablecarrier, i.e., one or more pharmaceutically acceptable carriersubstances and/or additives.

Thus, a subject of the invention is, for example, said compound and itspharmaceutically acceptable salts for use as a pharmaceutical,pharmaceutical compositions which comprise as active component aneffective dose of said compound and/or a pharmaceutically acceptablesalt thereof and a customary pharmaceutically acceptable carrier, andthe uses of said compound and/or a pharmaceutically acceptable saltthereof in the therapy or prophylaxis of the abovementioned syndromes aswell as their use for preparing medicaments for these purposes.

The pharmaceutical compositions according to the invention can beadministered orally, for example in the form of pills, tablets,lacquered tablets, sugar-coated tablets, granules, hard and soft gelatincapsules, aqueous, alcoholic or oily solutions, syrups, emulsions orsuspensions, or rectally, for example in the form of suppositories.Administration can also be carried out parenterally, for examplesubcutaneously, intramuscularly or intravenously in the form ofsolutions for injection or infusion. Other suitable administration formsare, for example, percutaneous or topical administration, for example inthe form of ointments, tinctures, sprays or transdermal therapeuticsystems, or the inhalative administration in the form of nasal sprays oraerosol mixtures, or, for example, microcapsules, implants or rods. Thepreferred administration form depends, for example, on the disease to betreated and on its severity.

The amount of active compound of Formulas I to I-d and/or itspharmaceutically acceptable salts in the pharmaceutical compositionnormally is from 0.1 to 200 mg, preferably from 1 to 200 mg, per dose,but depending on the type of the pharmaceutical composition it can alsobe higher. The pharmaceutical compositions usually comprise 0.5 to 90percent by weight of the compounds of Formulas I to I-d and/or theirpharmaceutically acceptable salts. The preparation of the pharmaceuticalcompositions can be carried out in a manner known per se. For thispurpose, one or more compounds of Formulas I to I-d and/or theirpharmaceutically acceptable salts, together with one or more solid orliquid pharmaceutical carrier substances and/or additives (or auxiliarysubstances) and, if desired, in combination with other pharmaceuticallyactive compounds having therapeutic or prophylactic action, are broughtinto a suitable administration form or dosage form which can then beused as a pharmaceutical in human or veterinary medicine.

For the production of pills, tablets, sugar-coated tablets and hardgelatin capsules, it is possible to use, for example, lactose, starch,for example maize starch, or starch derivatives, talc, stearic acid orits salts, etc. Carriers for soft gelatin capsules and suppositoriesare, for example, fats, waxes, semisolid and liquid polyols, natural orhardened oils, etc. Suitable carriers for the preparation of solutions,for example of solutions for injection, or of emulsions or syrups are,for example, water, physiologically acceptable sodium chloride solution,alcohols such as ethanol, glycerol, polyols, sucrose, invert sugar,glucose, mannitol, vegetable oils, etc. It is also possible tolyophilize the compounds of Formulas I to I-d and their pharmaceuticallyacceptable salts and to use the resulting lyophilisates, for example,for preparing preparations for injection or infusion. Suitable carriersfor microcapsules, implants or rods are, for example, copolymers ofglycolic acid and lactic acid.

Besides the active compounds and carriers, the pharmaceuticalcompositions can also contain customary additives, for example fillers,disintegrants, binders, lubricants, wetting agents, stabilizers,emulsifiers, dispersants, preservatives, sweeteners, colorants,flavorings, aromatizers, thickeners, diluents, buffer substances,solvents, solubilizers, agents for achieving a depot effect, salts foraltering the osmotic pressure, coating agents or antioxidants.

The dosage of the active compound of Formulas I to I-d and/or of apharmaceutically acceptable salt thereof to be administered depends onthe individual case and is, as is customary, to be adapted to theindividual circumstances to achieve an optimum effect. Thus, it dependson the nature and the severity of the disorder to be treated, and alsoon the sex, age, weight and individual responsiveness of the human oranimal to be treated, on the efficacy and duration of action of thecompounds used, on whether the therapy is acute or chronic orprophylactic, or on whether other active compounds are administered inaddition to compounds of Formulas Ito I-d. In general, a daily dose ofapproximately 0.01 to 100 mg/kg, preferably 0.01 to 10 mg/kg, inparticular 0.3 to 5 mg/kg (in each case mg per kg of bodyweight) isappropriate for administration to an adult weighing approximately 75 kgin order to obtain the desired results. The daily dose can beadministered in a single dose or, in particular when larger amounts areadministered, be divided into several, for example two, three or fourindividual doses. In some cases, depending on the individual response,it may be necessary to deviate upwards or downwards from the given dailydose. A single daily dose is preferred.

The compounds of Formulas I to I-d activate soluble guanylate cyclase.On account of this property, apart from use as pharmaceutically activecompounds in human medicine and veterinary medicine, they can also beemployed as a scientific tool or as an aid for biochemicalinvestigations in which such an effect on soluble guanylate cyclase isintended, and also for diagnostic purposes, for example in the in vitrodiagnosis of cell samples or tissue samples. The compounds of Formulas Ito I-d and salts thereof can furthermore be employed, as alreadymentioned above, as intermediates for the preparation of otherpharmaceutically active compounds.

One or more additional pharmacologically active agents may beadministered in combination with a compound of Formulas I to I-d. Anadditional active agent (or agents) is intended to mean apharmaceutically active agent (or agents) that is active in the body,including pro-drugs that convert to pharmaceutically active form afteradministration, which are different from the compound of Formulas I toI-d, and also includes free-acid, free-base and pharmaceuticallyacceptable salts of said additional active agents. Generally, anysuitable additional active agent or agents, including but not limited toanti-hypertensive agents, anti-atherosclerotic agents such as a lipidmodifying compound, anti-diabetic agents and/or anti-obesity agents maybe used in any combination with the compound of Formulas I to I-d in asingle dosage formulation (a fixed dose drug combination), or may beadministered to the patient in one or more separate dosage formulationswhich allows for concurrent or sequential administration of the activeagents (co-administration of the separate active agents). Examples ofadditional active agents which may be employed include but are notlimited to angiotensin converting enzyme inhibitors (e.g, alacepril,benazepril, captopril, ceronapril, cilazapril, delapril, enalapril,enalaprilat, fosinopril, imidapril, lisinopril, moveltipril,perindopril, quinapril, ramipril, spirapril, temocapril, ortrandolapril), angiotensin II receptor antagonists (e.g., losartan i.e.,COZAAR®, valsartan, candesartan, olmesartan, telmesartan and any ofthese drugs used in combination with hydrochlorothiazide such asHYZAAR®); neutral endopeptidase inhibitors (e.g., thiorphan andphosphoramidon), aldosterone antagonists, aldosterone synthaseinhibitors, renin inhibitors (e.g. urea derivatives of di- andtri-peptides (See U.S. Pat. No. 5,116,835), amino acids and derivatives(U.S. Pat. Nos. 5,095,119 and 5,104,869), amino acid chains linked bynon-peptidic bonds (U.S. Pat. No. 5,114,937), di- and tri-peptidederivatives (U.S. Pat. No. 5,106,835), peptidyl amino diols (U.S. Pat.Nos. 5,063,208 and 4,845,079) and peptidyl beta-aminoacyl aminodiolcarbamates (U.S. Pat. No. 5,089,471); also, a variety of other peptideanalogs as disclosed in the following U.S. Pat. Nos. 5,071,837;5,064,965; 5,063,207; 5,036,054; 5,036,053; 5,034,512 and 4,894,437, andsmall molecule renin inhibitors (including diol sulfonamides andsulfinyls (U.S. Pat. No. 5,098,924), N-morpholino derivatives (U.S. Pat.No. 5,055,466), N-heterocyclic alcohols (U.S. Pat. No. 4,885,292) andpyrolimidazolones (U.S. Pat. No. 5,075,451); also, pepstatin derivatives(U.S. Pat. No. 4,980,283) and fluoro- and chloro-derivatives ofstatone-containing peptides (U.S. Pat. No. 5,066,643), enalkrein, RO42-5892, A 65317, CP 80794, ES 1005, ES 8891, SQ 34017, aliskiren(2(S),4(S),5(S),7(S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)-phenyl]-octanamidhemifumarate) SPP600, SPP630 and SPP635), endothelin receptorantagonists, phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalfiland vardenafil), vasodilators, calcium channel blockers (e.g.,amlodipine, nifedipine, veraparmil, diltiazem, gallopamil, niludipine,nimodipins, nicardipine), potassium channel activators (e.g.,nicorandil, pinacidil, cromakalim, minoxidil, aprilkalim, loprazolam),diuretics (e.g., hydrochlorothiazide), sympatholitics, beta-adrenergicblocking drugs (e.g., propranolol, atenolol, bisoprolol, carvedilol,metoprolol, or metoprolol tartate), alpha adrenergic blocking drugs(e.g., doxazocin, prazocin or alpha methyldopa) central alpha adrenergicagonists, peripheral vasodilators (e.g. hydralazine); lipid loweringagents e.g., HMG-CoA reductase inhibitors such as simvastatin andlovastatin which are marketed as ZOCOR® and MEVACOR® in lactone pro-drugform and function as inhibitors after administration, andpharmaceutically acceptable salts of dihydroxy open ring acid HMG-CoAreductase inhibitors such as atorvastatin (particularly the calcium saltsold in LIPITOR®), rosuvastatin (particularly the calcium salt sold inCRESTOR®), pravastatin (particularly the sodium salt sold inPRAVACHOL®), and fluvastatin (particularly the sodium salt sold inLESCOL®); a cholesterol absorption inhibitor such as ezetimibe (ZETIA®)and ezetimibe in combination with any other lipid lowering agents suchas the HMG-CoA reductase inhibitors noted above and particularly withsimvastatin (VYTORIN®) or with atorvastatin calcium; niacin inimmediate-release or controlled release forms, and/or with an HMG-CoAreductase inhibitor; niacin receptor agonists such as acipimox andacifran, as well as niacin receptor partial agonists; metabolic alteringagents including insulin and insulin mimetics (e.g., insulin degludec,insulin glargine, insulin lispro), dipeptidyl peptidase-IV (DPP-4)inhibitors (e.g., sitagliptin, alogliptin, omarigliptin, linagliptin,vildagliptin); insulin sensitizers, including (i) PPARγ agonists, suchas the glitazones (e.g. pioglitazone, AMG 131, MBX2044, mitoglitazone,lobeglitazone, IDR-105, rosiglitazone, and balaglitazone), and otherPPAR ligands, including (1) PPARα/γ dual agonists (e.g., ZYH2, ZYH1,GFT505, chiglitazar, muraglitazar, aleglitazar, sodelglitazar, andnaveglitazar); (2) PPARα agonists such as fenofibric acid derivatives(e.g., gemfibrozil, clofibrate, ciprofibrate, fenofibrate, bezafibrate),(3) selective PPARy modulators (SPPARγM's), (e.g., such as thosedisclosed in WO 02/060388, WO 02/08188, WO 2004/019869, WO 2004/020409,WO 2004/020408, and WO 2004/066963); and (4) PPARγ partial agonists;(ii) biguanides, such as metformin and its pharmaceutically acceptablesalts, in particular, metformin hydrochloride, and extended-releaseformulations thereof, such as Glumetza™, Fortamet™, and GlucophageXR™;and (iii) protein tyrosine phosphatase-1B (PTP-1B) inhibitors (e.g.,ISIS-113715 and TTP814); insulin or insulin analogs (e.g., insulindetemir, insulin glulisine, insulin degludec, insulin glargine, insulinlispro and inhalable formulations of each); leptin and leptinderivatives and agonists; amylin and amylin analogs (e.g., pramlintide);sulfonylurea and non-sulfonylurea insulin secretagogues (e.g.,tolbutamide, glyburide, glipizide, glimepiride, mitiglinide,meglitinides, nateglinide and repaglinide); α-glucosidase inhibitors(e.g., acarbose, voglibose and miglitol); glucagon receptor antagonists(e.g., MK-3577, MK-0893, LY-2409021 and KT6-971); incretin mimetics,such as GLP-1, GLP-1 analogs, derivatives, and mimetics; and GLP-1receptor agonists (e.g., dulaglutide, semaglutide, albiglutide,exenatide, liraglutide, lixisenatide, taspoglutide, CJC-1131, andBIM-51077, including intranasal, transdermal, and once-weeklyformulations thereof); LDL cholesterol lowering agents such as (i)HMG-CoA reductase inhibitors (e.g., simvastatin, lovastatin,pravastatin, cerivastatin, fluvastatin, atorvastatin, and rosuvastatin),(ii) bile acid sequestering agents (e.g., colestilan, colestimide,colesevalam hydrochloride, colestipol, cholestyramine, anddialkylaminoalkyl derivatives of a cross-linked dextran), (iii)inhibitors of cholesterol absorption, (e.g., ezetimibe), and (iv) acylCoA:cholesterol acyltransferase inhibitors, (e.g., avasimibe);HDL-raising drugs, (e.g., niacin and nicotinic acid receptor agonists,and extended-release versions thereof); antiobesity compounds; agentsintended for use in inflammatory conditions, such as aspirin,non-steroidal anti-inflammatory drugs or NSAIDs, glucocorticoids, andselective cyclooxygenase-2 or COX-2 inhibitors; glucokinase activators(GKAs) (e.g., AZD6370); inhibitors of 11β-hydroxysteroid dehydrogenasetype 1, (e.g., such as those disclosed in U.S. Pat. No. 6,730,690, andLY-2523199); CETP inhibitors (e.g., anacetrapib, evacetrapib, andtorcetrapib); inhibitors of fructose 1,6-bisphosphatase, (e.g., such asthose disclosed in U.S. Pat. Nos. 6,054,587; 6,110,903; 6,284,748;6,399,782; and 6,489,476); inhibitors of acetyl CoA carboxylase-1 or 2(ACCl or ACC2); AMP-activated Protein Kinase (AMPK) activators; otheragonists of the G-protein-coupled receptors: (i) GPR-109, (ii) GPR-119(e.g., MBX2982 and PSN821), and (iii) GPR-40; SSTR3 antagonists (e.g.,such as those disclosed in WO 2009/001836); neuromedin U receptoragonists (e.g., such as those disclosed in WO 2009/042053, including,but not limited to, neuromedin S (NMS)); SCD modulators; GPR-105antagonists (e.g., such as those disclosed in WO 2009/000087); SGLTinhibitors (e.g., ASP1941, SGLT-3, empagliflozin, dapagliflozin,ertugliflozin, canagliflozin, BI-10773, PF-04971729, remogloflozin,TS-071, tofogliflozin, ipragliflozin, and LX-4211); inhibitors of acylcoenzyme A:diacylglycerol acyltransferase 1 and 2 (DGAT-1 and DGAT-2);inhibitors of fatty acid synthase; inhibitors of acyl coenzymeA:monoacylglycerol acyltransferase 1 and 2 (MGAT-1 and MGAT-2); agonistsof the TGRS receptor (also known as GPBAR1, BG37, GPCR19, GPR131, andM-BAR); ileal bile acid transporter inhibitors; PACAP, PACAP mimetics,and PACAP receptor 3 agonists; PPAR agonists; protein tyrosinephosphatase-1B (PTP-1B) inhibitors; IL-1b antibodies, (e.g., XOMA052 andcanakinumab); and bromocriptine mesylate and rapid-release formulationsthereof; or with other drugs beneficial for the prevention or thetreatment of the above-mentioned diseases including nitroprusside anddiazoxide the free-acid, free-base, and pharmaceutically acceptable saltforms of the above active agents where chemically possible.

The following examples are provided so that the invention might be morefully understood. Unless otherwise indicated, the starting materials arecommercially available. They should not be construed as limiting theinvention in any way.

Several methods for preparing the compounds of this invention aredescribed in the following Schemes and Examples. Starting materials andintermediates are purchased, made from known procedures, or as otherwiseillustrated. Some frequently applied routes to the compounds of FormulaS-I are also described by the Schemes as follows. In some cases theorder of carrying out the steps of reaction schemes may be varied tofacilitate the reaction or to avoid unwanted reaction products. The “R”and “X” groups in the Schemes correspond to the variables defined inFormula S-I at the same positions on the structures.

Compounds of Formula S-I, S-II and S-III can be prepared according tothe sequence as depicted in Scheme 1. Conversion of thetriazolo[1,5-a]pyrazine nitrile S-1a to the amidine intermediate S-1bcan be accomplished with a reagent such as amino(chloro)methylaluminum,prepared from trimethylaluminum and NH₄Cl, in a non-polar solvent suchas toluene at elevated temperature as described by Garigipati, R. S. etal Tetrahedron Letters 1990, 31, 1969. The nitrile S-1a can also beconverted to the amidine S-1b by using NaOMe in MeOH to form theimidate, which can then be transformed to the amidine S-1b using NH₄Cland acetic acid as described by Pinner, A. et al, Ber. Dtsch. Chem. Ges.1877, 10, 1889. Treatment of the amidine S-1b with a suitablemalononitrile intermediate S-1c in an alcoholic solvent, such as t-BuOH,and a suitable base such as NaHCO₃, KHCO₃, or Na₂CO₃ at elevatedtemperature provides compounds of Formula S-I. The reactions leading tocompounds of Formula S-I in Scheme 1 may also be carried out using thecorresponding methyl, ethyl, or propyl esters (R¹⁰) of compound S-1c.Treatment of compounds of Formula S-I with a suitable diazotizingreagent such as tert-butyl nitrite, isopentyl nitrite, or sodium nitritein a solvent such as 1,2-DCE, DMA, DMF, MeCN, or THF at elevatedtemperature provides compounds with Formula S-II and S-III. The ratio ofS-II and S-III varies depending on the structure of Formula S-I andwater content in the reaction.

Compounds of Formula S-II can be drawn in both tautomeric forms as shownin FIG. 1. Although the compounds are drawn in the alcohol formthroughout, the compounds can also be drawn in the keto form. Forexample, Example 170A is drawn in the alcohol form. However, Example170A could have been drawn in the keto form.

Compounds of Formula S-IV, can be prepared according to the sequence asdepicted in Scheme 2. Treatment of compounds of Formula S-I with asuitable diazotizing reagent such as tert-butyl nitrite, in presence ofa copper (II) salt such as CuCl₂ or CuBr₂ can afford halogenatedintermediate which can be transformed into the nitrile intermediate S-2ausing Zn(CN)₂ and a palladium catalyst such as Pd(dppf)Cl₂ at anelevated temperature. Compounds of Formula S-IV can be obtained by thetreatment of compound S-2a with an aq. HCl solution.

The nitrile intermediate S-1a can be prepared by two different routes asdepicted in Scheme 3. In the first route6,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazine S-3a can be selectivelycoupled to an alkylzinc reagent, R¹ZnX, using a palladium catalyst suchas Pd(PPh₃)₂Cl₂ to give compound S-3b, which can be transformed into thenitrile intermediate S-1a using Zn(CN)₂ and a palladium catalyst such asPd(dppf)Cl₂ at an elevated temperature. Alternatively, nitrileintermediate S-1a can be obtained from 3,5-dihalopyrazin-2-amine S-3csuch as 3,5-dichloropyrazin-2-amine or 3,5-dibromopyrazin-2-amine, viaroute 2. Treatment of S-3c with an alkylzinc reagent, R₁ZnX, using apalladium catalyst such as Pd(PPh₃)₂Cl₂ affords S-3d, which can betranformed into compound S-3f by condensation with amide S-3e. Treatmentof compound S-3f with hydroxylamine hydrochloride followed bytrifluoroacetic anhydride (TFAA) affords the triazolo[1,5-a]pyrazineS-3g. Compound S-3g can be transformed into the nitrile intermediateS-1a using Zn(CN)₂ and a palladium catalyst such as Pd(dppf)Cl₂ at anelevated temperature.

In one embodiment of the present invention, compounds with Formula S-Vmay be prepared by the sequence depicted in Scheme 4. The amidineintermediate S-1b from Scheme 1 can be cyclized with a suitablediester-malononitrile intermediate (S-4a) to afford compound S-4b.Treatment of the ester intermediate S-4b with hydrazine affords the acylhydrazide intermediate S-4c, which can be acylated with a suitableacylating reagent bearing the desired R⁶ substitution and subsequentlycan be cyclized in the presence of a suitable condensing reagent such aspolyphosphoric acid (PPA) to form a 1,3,4-oxadiazole Formula S-V.

In one embodiment of the present invention, compounds with Formula S-VImay be prepared by the sequence outlined in Scheme 5. The amidineintermediate S-1b from Scheme 1 can be treated with a suitablemalononitrile reagent S-5a under similar conditions described for Scheme1 to afford the alkyne intermediate S-5b. The alkyne intermediate S-5bcan be further transformed into 1,2,3-triazoles with Formula S-VI bytreatment with a suitable alkyl azide that is either commerciallyavailable or formed in situ from sodium azide and an alkyl bromide or analkyl amine and imidazole-1-sulfonyl azide hydrochloride in the presenceof a suitable copper source such as copper(II) sulfate.

The preparation of compound S-1c is outlined in Scheme 6. Treatment ofdiethyl oxalate with a suitable aryl magnesium bromide (with or withoutLiCl additive) or the lithiate of heteroaryl reagents derived viametal-halogen exchange in a suitable solvent such as THF affordscompound S-6b. Treatment of compound S-6b with malononitrile and asuitable base such as piperidine in a solvent such as EtOH at elevatedtemperature affords compound S-6c. Compound S-6c, upon treatment with asuitable alkyl magnesium bromide (with or without LiCl additive) in asolvent such as THF affords compound S-1c.

In addition to the method described in Scheme 6, intermediates S-1c, mayalso be prepared as shown in Scheme 7. Deprotonation of ester S-7a usinga suitable base such as LiHMDS, NaHMDS, NaH or LDA in a solvent such asTHF or DMF followed by treatment with an alkyl iodide affords theintermediate S-7b. Treatment of intermediate S-7b with a suitablebrominating reagent such as NBS and AIBN in a solvent such as carbontetrachloride at refluxing temperatures affords intermediate S-7c.Intermediate S-7c can be transformed to compound S-1c by reaction withmalononitrile in the presence of a suitable base such as NaH, t-BuOK,K₂CO₃ or DBU in a solvent such as THF or DMF at RT or at elevatedtemperatures. The synthetic sequence depicted in Scheme 7 can be used toprepare the corresponding methyl, ethyl or propyl esters (R¹⁰) ofcompound S-1c.

The ester S-7a can be prepared according to Scheme 8 from thecorresponding carboxylic acid by one skilled in the art. The ester S-7amay also be prepared by the α-arylation/heteroarylation of esters asdescribed by Buchwald, S. L. et al Organic Letters 2009, 11, 1773; or byShen, H. C. et al Organic Letters 2006, 8, 1447. Commercially availablearyl bromides S-8a can be converted to compound S-7a (depicted as theethyl ester) by the reaction with diethyl malonate in the presence of asuitable catalyst system such as CuI and picolinic acid, followed bydecarboxylation at elevated temperatures.

Compounds of the present invention possess an asymmetric center at thecarbon bearing the R²/R³ substituent which can be either R or Sconfiguration. These enantiomeric mixtures may be separated or resolvedto single enantiomers using methods familiar to those skilled in theart. For example, compounds of the present invention may be resolved tothe pure isomers by using chiral SFC chromatography. Racemic materialcan be resolved to enantiomerically pure compounds whenever possible andat any step in the route. Characterization data may be of the chiral orracemic material.

The independent synthesis of diastereomers and enantiomers or theirchromatographic separations may be achieved using methods familiar tothose skilled in the art and by appropriate modification of themethodology disclosed herein. Their absolute stereochemistry may bedetermined by X-ray crystallography of crystalline products orcrystalline intermediates which are derivatized, if necessary, with areagent containing an asymmetric center of known absolutestereochemistry, or by vibrational circular dichroism (VCD)spectroscopy.

Throughout the synthetic schemes and examples, abbreviations andacronyms may be used with the following meanings unless otherwiseindicated:

AcOH=acetic acid; AIBN=2,2′-azobisisobutyronitrile; Anhydr.=Anhydrous;Aq.=aqueous; bp, b.p.=boiling point; br s=broad singlet; Bu=butyl;t-Bu=tert-butyl; BuLi=butyllithium; tBuOH, tert-BuOH=tert-butanol;tBuOK=potassium tert-butoxide; CDCl₃=deuterated chloroform;CD₃OD=Tetradeuteromethanol; CELITE=diatomaceous earth;CF₃=trifluoromethyl; cGMP=cyclic guanosine monophosphate; conc,conc.=concentrated, concentrate, concentrates;DBU=1,8-Diazabicyclo[4.3.0]undec-7-ene; DCM=dichloromethane; 1,2-DCE,DCE=1,2-dichloroethane; DIEA=diisopropylethylamine; DMA,DMAC=N,N-dimethylacetamide; DMF=N,N-dimethylformamide;DMF-DMA=N,N-Dimethylformamide dimethyl acetal; DMSO=dimethylsulfoxide;dppf=1,1′-bis(diphenylphosphino)ferrocene; EAB=egg albumin; EBSS=Earle'sbalanced salt solution; equiv, eq.=equivalent(s); Et=ethyl;Et₃N=triethylamine; EtOAc=ethyl acetate; EtOH=ethanol; GTP=guanosinetriphosphate; h, hr=hour;HATU=1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxidhexafluorophosphate; HCl=hydrogen chloride;HOBt=Hydroxybenzotriazole; HPLC=High pressure liquid chromatography;Int.=intermediate; iPr=isopropyl; IPA, i-PrOH=Isopropanol; LCMS,LC/MS=liquid chromatography-mass spectrometry; LDA=lithiumdiisopropylamide; LiHMDS, LHMDS=lithium bis(trimethylsilyl)amide; min,min.=minute; M=Molar; Me=methyl; MeCN=acetonitrile; MeI=methyl iodide;MeOH=methanol; mp, m.p.=melting point; mpk=milligrams per kilogram;N=Normal; N₂=nitrogen; NaOMe=sodium methoxide; NCS=N-chloro succinimide;NMP=N-methylpyrrolidone; NBS=N-bromo succinimide; NaHMDS=sodiumbis(trimethylsilyl)amide; NMR=nuclear magnetic resonance; N.D.=notdetermined; PDA=photodiode array;Pd(dppf)Cl₂=dichloro((1,1′-bis(diphenylphosphino)ferrocene)palladium(II); Pd(PPh₃)₂Cl₂=dichlorobis(triphenylphosphine)palladium(II) orbis(triphenylphosphine) palladium (II) chloride;Pd₂(dba)₃=tris(dibenzylideneacetone)dipalladium (0); Ph=phenyl;PPA=polyphosphoric acid; Pr=propyl; psig=pounds per square inch gauge;PTFE=polytetrafluoroethylene; PTLC, prep TLC=preparative thin layerchromatography; PyBOP=(benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate; rac=racemic; rt=retention time; RP-HPLC=reversephase HPLC; RT=room temperature; sat., sat'd=saturated;SFC=supercritical fluid chromatography; sGC=soluble guanylate cyclase;TFA=trifluoroacetic acid; TFAA=trifluoroacetic anhydride; TLC=thin layerchromatography; THF=tetrahydrofuran; VCD=vibrational circular dichroism;v, v/v=volume, volume to volume; w, w/w=weight, weight to weight.

The following examples are provided to more fully illustrate the presentinvention, and shall not be construed as limiting the scope in anymanner. Unless stated otherwise, the following conditions were employed.All operations were carried out at room or ambient temperature (RT),that is, at a temperature in the range 18-25° C. Reactions are generallydone using commercially available anhydrous solvents under an inertatmosphere, either nitrogen or argon. Microwave reactions were doneusing a BIOTAGE Initiator™ or CEM EXPLORER® system. Evaporation ofsolvent was carried out using a rotary evaporator under reduced pressure(4.5-30 mmHg) with a bath temperature of up to 50° C. The course ofreactions was followed by thin layer chromatography (TLC) and/or tandemhigh performance liquid chromatography (HPLC) followed by electron spraymass spectroscopy (MS), herein termed LCMS, and any reaction times aregiven for illustration only. The structure of all final compounds wasassured by at least one of the following techniques: MS or protonnuclear magnetic resonance (¹H NMR) spectrometry, and the purity wasassured by at least one of the following techniques: TLC or HPLC. ¹H NMRspectra were recorded on either a Varian Unity or a Varian Inovainstrument at 300, 400, 500 or 600 MHz using the indicated solvent. Whenline-listed, NMR data are in the form of delta values for majordiagnostic protons, given in parts per million (ppm) relative toresidual solvent peaks (multiplicity and number of hydrogens).Conventional abbreviations used for signal shape are: s. singlet; d.doublet (apparent); t. triplet (apparent); m. multiplet; br. broad; etc.MS data were recorded on a Waters Micromass unit, interfaced with aHewlett-Packard (AGILENT 1100) HPLC instrument, and operating onMASSLYNX/OpenLynx software. Electrospray ionization was used withpositive (ES+) or negative ion (ES−) detection; and diode arraydetection. Purification of compounds by preparative reverse phase HPLCwas performed on a GILSON system using a YMC-Pack Pro C18 column (150×20mm i.d.) eluting at 20 mL/min with a water/acetonitrile (0.1% TFA)gradient (typically 5% acetonitrile to 95% acetonitrile) using a SUNFIREPrep C18 OBD 5 μM column (100×30 mm i.d.) eluting at 50 mL/min with awater/acetonitrile (0.1% TFA) gradient. Purification of compounds bypreparative thin layer chromatography (PTLC) was conducted on 20×20 cmglass plates coated with silica gel, commercially available fromAnaltech; or E. Merck. Flash column chromatography was carried out on aglass silica gel column using Kieselgel 60, 0.063-0.200 mm (SiO₂), or ona BIOTAGE SiO₂ cartridge system using the BIOTAGE Horizon and BIOTAGESP-1 systems; or a Teledyne Isco SiO₂ cartridge using the COMBIFLASH Rfsystem. Chemical symbols have their usual meanings, and the followingabbreviations have also been used: h or hr (hours), min (minutes), v(volume), w (weight), b.p. (boiling point), m.p. (melting point), L(litre(s)), mL (millilitres), g (gram(s)), mg (milligrams(s)), mol(moles), mmol (millimoles), eq or equiv (equivalent(s)), μM(micromolar), nM (nanomolar), ca (circa/about).

The following are representative procedures for the preparation ofintermediates used to prepare the final products described in theExamples that follow thereafter. These examples are provided for thepurpose of further illustration only and are not intended to belimitations on the disclosed invention.

It is understood that a chiral center in a compound may exist in the “S”or “R” stereo-configurations, or as a mixture of both. In some of theexamples for intermediate compounds and final compounds, such compoundshaving a racemic chiral center were separated into individualstereoisomers, for example, referred to as isomer A (or enantiomer A orthe like), which refers to the observed faster eluting isomer, andisomer B (or enantiomer B or the like), which refers to the observedslower eluting isomer, and each such isomer may be noted in the exampleas either the fast or slow eluting isomer. When a single “A” or “B”isomer intermediate is used to prepare a downstream compound, thedownstream compound may take the “A” or “B” designation that correspondsto the previously used intermediate.

Any Intermediates described below may be referred to herein by theirnumber preceded by “I-.” For illustration, the racemic parent titlecompound would be referred to as Intermediate 39 (I-39, or rac I-39),and the separated stereoisomers are noted as Intermediates 39A and 39B(or I-39A and I-39B). In some examples, compounds having a chiral centerwere derived synthetically from a single isomer intermediate; e.g.,Example 63 was made using stereoisomer I-2A. Absolute stereochemistry (Ror S) of each of the separated isomers was not determined, unlessspecifically described. An asterisk (*) may be used in a chemicalstructure drawing that indicates the location of a chiral center.

Absolute stereochemistry of separate stereoisomers in the Examples andIntermediates was not determined unless stated otherwise in an Exampleor Intermediate synthesis.

Intermediate 1, 1A and 1B and the S and R Isomers Ethyl3,3-dicyano-2-(4-fluorophenyl)-2-methylpropanoate

-   Step A—Ethyl 2-(4-fluorophenyl)-2-oxoacetate: Into a flask was    placed a solution of diethyl oxalate (28.5 g, 195 mmol) in THF (300    mL) which was cooled at −78° C. 4-fluorophenylmagnesium bromide (150    mL, 1.0 M in THF) was added dropwise, and the resulting solution was    stirred for 1.5 h with warming to RT. The reaction was quenched by    the addition of sat. aq. NH₄Cl. The resulting solution was extracted    with EtOAc (3×) and the organic layers were combined, dried over    anhydr. Na₂SO₄, and filtered. The filtrate was conc. in vacuo to    dryness. The residue was purified by silica gel chromatography with    EtOAc:petroleum ether (1%) to afford the title compound.-   Step B—Ethyl 3,3-dicyano-2-(4-fluorophenyl)acrylate: Into a flask    was placed the intermediate from Step A (28.0 g, 143 mmol),    malononitrile (37.7 g, 571 mmol), piperidine (2.5 mL), and EtOH (125    mL). The resulting solution was stirred at reflux for 16 h. Upon    completion, the resulting mixture was conc. in vacuo. The residue    was purified by silica gel chromatography with EtOAc:petroleum ether    (10%) to afford the title compound.-   Step C—Ethyl 3,3-dicyano-2-(4-fluorophenyl)-2-methylpropanoate: Into    a flask was placed the intermediate from Step B (3.0 g, 12 mmol),    THF (50 mL), and lithium chloride (1.0 g, 23.6 mmol) which was    cooled at 0° C. Subsequently, methylmagnesium bromide (7 mL) was    added dropwise, and the resulting solution was stirred for 1 h at    0° C. The reaction was then quenched by the addition of water. The    resulting solution was extracted with EtOAc (2×). The organic layers    were combined, dried over anhydr. Na₂SO₄, and filtered. The filtrate    was conc. in vacuo to dryness. The residue was purified by silica    gel chromatography with EtOAc:petroleum ether (25%) to afford the    racemic title compound I-1. The racemic material was resolved using    chiral SFC (OJ column) to afford isomers I-1A (faster eluting) and    I-1B (slower eluting) of the title compound. ¹H NMR (300 MHz,    CDCl₃): δ 7.40-7.33 (2H, m), 7.17-7.09 (2H, m), 4.45 (1H, s), 4.30    (2H, q, J=7.2 Hz), 1.99 (3H, s), 1.26 (3H, t, J=7.2 Hz).

Using a similar procedure to that described in Intermediate 1, thefollowing compounds in Table 1 were prepared using either commercialstarting reagents or from compounds known in the literature.

TABLE 1

Chiral Resolution Int Column R₃ m/z (M + H) or ¹H NMR I-2A and 2BCHIRALCEL OJ

275 [M − 1]⁻ I-3A and 3B CHIRALPAK IA

¹H NMR (400 MHz, DMSO-d₆): δ 7.89 (2H, d, J = 8.4 Hz), 7.67 (2H, d, J =8.4 Hz) 5.83 (1H, s), 4.28 (2H, q, J = 7.2 Hz), 1.89 (3H, s), 1.19 (3H,t, J = 7.2 Hz) I-4A and B CHIRALPAK AD

293 [M − 1]⁻ I-5A and B CHIRALPAK AD

¹H NMR (300 MHz, CDCl₃): δ 7.31-7.12 (3H, m), 4.46 (1H, s), 4.31 (2H, q,J = 7.2 Hz), 1.99 (3H, s), 1.28 (3H, t, J = 7.2 Hz) I-6A and BPHENOMENEX LUX 5U CELLULOSE-3

293 [M − 1]⁻ I-7A and B CHIRALPAK IA

¹H NMR (300 MHz, CDCl₃): δ 7.43 (1 H, td, J = 8.11, 5.97 Hz), 7.07-7.16(3 H, m), 4.49 (1 H, s), 3.82 (3 H, s), 2.00 (3 H, s).

Intermediate 8, 8A and 8B Ethyl3,3-dicyano-2-(5-fluoropyridin-2-yl)-2-methylpropanoate and S and RIsomers Thereof

-   Step A—Diethyl 2-(5-fluoropyridin-2-yl)malonate: Into a flask was    placed 2-bromo-5-fluoropyridine (20.0 g, 114 mmol), 1,3-diethyl    propanedioate (54.5 g, 340 mmol), picolinic acid (5.6 g, 45 mmol),    Cs₂CO₃ (143 g, 438 mmol), CuI (4.3 g, 23 mmol), and 1,4-dioxane (500    mL). The resulting solution was stirred for 12 h at 100° C. The    mixture was quenched by the addition of water (300 mL). The    resulting solution was extracted with EtOAc (2×), the organic layers    combined and dried over anhydr. Na₂SO₄, and conc. in vacuo to    dryness. The residue was purified by silica gel chromatography using    EtOAc:petroleum ether (0-20%) to afford the title compound.-   Step B—Ethyl 2-(5-fluoropyridin-2-yl)acetate: Into a flask was    placed the intermediate from Step A (46 g, crude), NaCl (20 g, 342    mmol), water (6 mL), and DMSO (90 mL). The mixture was stirred for 3    h at 180° C. Upon completion, the resulting solution was diluted    with EtOAc, washed with water (5×) and the organic layer was dried    over anhydr. Na₂SO₄ and conc. in vacuo to dryness. The residue was    purified by silica gel chromatography using EtOAc:petroleum ether    (0-20%) to afford the title compound.-   Step C—Ethyl 2-(5-fluoropyridin-2-yl)propanoate: Into a flask was    placed THF (200 mL) and LiHMDS (45 mL, 1.0 M). This was followed by    dropwise addition of the intermediate from Step B (7.5 g, 41 mmol)    with stirring at 0° C. After stirring the resulting solution for 1    h, a solution of iodomethane (5.8 g, 41 mmol) in THF (10 mL) was    added dropwise. The resulting solution was stirred for 3 h at 0° C.    The reaction was then quenched by the addition of water. The    resulting mixture was extracted with EtOAc (3×), the organic layers    combined and dried over anhydr. Na₂SO₄, and conc. in vacuo to    dryness. The residue was purified by silica gel chromatography using    EtOAc:petroleum ether (0-20%) to afford the title compound.-   Step D—Ethyl 2-bromo-2-(5-fluoropyridin-2-yl)propanoate: Into a    flask was added the intermediate from Step C (1 g, 5 mmol) and THF    (50 mL). This was followed by the addition of LiHMDS (5 mL, 1.0 M)    dropwise with stirring at −78° C. The resulting solution was stirred    for 30 min at −78° C. before NBS (1.2 g, 7.1 mmol) in THF (10 mL)    was added, and the solution was warmed to RT and stirred for 1 h.    The reaction was then quenched by the addition of water. The    resulting solution was extracted with EtOAc (3×) and the organic    layers combined and dried over anhydr. Na₂SO₄. The solid was    filtered and the filtrate was conc. in vacuo to dryness. The residue    was purified by silica gel chromatography using EtOAc:petroleum    ether (0-10%) to afford the title compound.-   Step E—Ethyl    3,3-dicyano-2-(5-fluoropyridin-2-yl)-2-methylpropanoate: Into a    flask was placed DMF (20 mL) and sodium hydride (260 mg, 6.50 mmol,    60%). This was followed by the addition of malononitrile (460 mg,    6.96 mmol) with stirring at 0° C. The resulting solution was stirred    for 30 min at 0° C. To this was added the intermediate from Step D    (950 mg, 3.44 mmol) in DMF dropwise with stirring at 0° C. The    resulting solution was stirred for 1 h at RT. Upon completion, the    resulting solution was quenched with water, and extracted with    EtOAc. The organic layer was dried over anhydr. Na₂SO₄ and conc. in    vacuo to dryness. The residue was purified by silica gel    chromatography using EtOAc:petroleum ether (0-20%). The racemic    material was resolved using a chiral SFC (IA column) to afford    isomers I-8A (faster eluting) and I-8B (slower eluting) of the title    compound. ¹H NMR (300 MHz, CDCl₃): δ 8.45-8.44 (1H, dd, J=0.9, 2.4    Hz), 7.57-7.47 (2H, m), 5.17 (1H, s), 4.29-4.19 (2H, m), 2.00 (3H,    s), 1.27-1.22 (3H, t, J=6.9 Hz).

Using a similar procedure for the preparation of Intermediate 8, thefollowing intermediates in Table 2 were prepared.

TABLE 2

Chiral Resolution Int. Column R₃ R m/z (M + H) or ¹H NMR I-9A and  9BCHIRALPAK IA

Et 278.2 I-10A and 10B CHIRALPAK AD-H

Et 274.0 I-11A and 11B CHIRALPAK AD

Me ¹H NMR (500 MHz, CDCl₃): δ 7.44- 7.42 (3H, m), 7.38-7.36 (2H, m),4.50 (1H, s), 3.80 (3H, s), 2.00 (3H, s). I-12A and 12B CHIRALCEL OJ

Et 259 [M − 1]⁻ I-13A and 13B CHIRALPAK IA

Et 312.0 I-14A and 14B CHIRALPAK IA

Et 258   I-15A and 15B CHIRALPAK AS

Et 269.1 I-16A and 16B PHENO LUX CELLULOSE- 2

Et 247.1

Intermediate 17, 17A and 17B and the S and R Isomers Thereof

Ethyl 3,3-dicyano-2-methyl-2-(5-(trifluoromethyl)pyrimidin-2-yl)

-   Step A—Diethyl 2-(5-iodopyrazin-2-yl)malonate: To a flask was added    2-bromo-5-iodopyrazine (3.0 g, 10.53 mmol), diethyl malonate (3.5 g,    22.11 mmol), potassium carbonate (3.0 g, 21.59 mmol), and DMSO (20    mL). The resulting mixture was stirred for 16 h at 80° C., then    cooled to RT and quenched by the addition of sat. aq. NH₄Cl. The    mixture was extracted with EtOAc (3×). The organic layer was washed    with brine, dried over anhydr. Na₂SO₄, and filtered. The filtrate    was conc. in vacuo to dryness. The residue was purified by silica    gel column chromatography with EtOAc:petroleum ether (10-20%) to    afford the title compound.-   Step B—Diethyl 2-(5-(trifluoromethyl)pyrazin-2-yl)malonate: To a    flask, under an inert atmosphere of nitrogen, was added copper(I)    iodide (6.15 g, 32 3 mmol), potassium fluoride (1.75 g, 30 1 mmol)    (dried in vacuo at 200° C. for 30 min),    trimethyl(trifluoromethyl)silane (3.45 g, 24.3 mmol), and    N-methyl-2-pyrrolidinone (80 mL). The mixture was heated to 50° C.    over 30 min and stirred for 5 min before diethyl    2-(5-iodopyrazin-2-yl)malonate (7.3 g, 14.0 mmol) in    N-methyl-2-pyrrolidinone (10 mL) was added. The resulting mixture    was stirred for 6 h at 50° C. The reaction mixture was cooled to RT    and quenched by the addition of NH₄OH (10%). The mixture was    extracted with EtOAc (3×). The organic layer was washed with NH₄OH    (10%) and brine, dried over anhydr. Na₂SO₄, and filtered. The    filtrate was conc. in vacuo. The residue was purified by silica gel    column chromatography with EtOAc:petroleum ether (5-20%) to afford    the title compound.-   Step C—Synthesis of ethyl    2-(5-(trifluoromethyl)pyrazin-2-yl)acetate: To a flask, under an    inert atmosphere of nitrogen, was added diethyl    2-(5-(trifluoromethyl)pyrazin-2-yl)malonate (3.8 g, 12.4 mmol),    dimethyl sulfoxide (40 mL), water (0.34 mL, 18 6 mmol), and sodium    chloride (1.09 mL, 18.6 mmol). The resulting mixture was stirred at    150° C. for 1 h, then allowed to cool down to RT. The resulting    mixture was diluted with EtOAc, the organic layer was washed with    brine (2×), dried over anhydr. Na₂SO₄, and filtered. The filtrate    was conc. in vacuo. The residue was purified by silica gel column    chromatography with EtOAc:petroleum ether (0-20%). The crude product    was applied onto a C18 column with water:acetonitrile (with 0.05%    ammonium bicarbonate) (30-70%). The residue was extracted with EtOAc    (3×). The organic layer was dried over anhydr. Na₂SO₄, and filtered.    The filtrate was conc. in vacuo, to afford the title compound.-   Step D—Ethyl 2-(5-(trifluoromethyl)pyrazin-2-yl)propanoate: To a    flask, under an inert atmosphere of nitrogen, was added ethyl    2-(5-(trifluoromethyl)pyrazin-2-yl)acetate (700 mg, 2.60 mmol) and    THF (14 mL). The resulting mixture was cooled to 0° C., and    bis(trimethylsilyl)amide (2.86 mL, 2.86 mmol) was added dropwise.    The resulting mixture was stirred for 1 h at 0° C. before MeI (0.16    mL, 2.60 mmol) was added dropwise. The resulting mixture was stirred    for 1 h at 0° C. then 3 h at RT. The reaction mixture was quenched    by the addition of sat. aq. NH₄Cl. The mixture was extracted with    EtOAc (3×). The organic layer was washed with brine, dried over    anhydr. Na₂SO₄, and filtered. The filtrate was conc. in vacuo. The    residue was purified by silica gel column chromatography with    EtOAc:petroleum ether (0-10%) to afford the title compound.-   Step E—Ethyl 2-bromo-2-(5-(trifluoromethyl)pyrazin-2-yl)propanoate:    To a flask, under an inert atmosphere of nitrogen, was added ethyl    2-(5-(trifluoromethyl)pyrazin-2-yl)propanoate (280 mg, 0.98 mmol)    and THF (8 mL). The resulting mixture was cooled to 0° C. and    bis(trimethylsilyl)amide (1.47 mL, 1.47 mmol, 1.5 equiv) was added    dropwise. The resulting mixture was stirred for 1 h at 0° C. before    1-bromopyrrolidine-2,5-dione (262 mg, 1.47 mmol) in THF (4 mL) RT    and stirred for 1 h. The reaction mixture was quenched by the    addition of sat. aq. NH₄Cl. The mixture was extracted with EtOAc    (3×). The organic layer was washed with brine, dried over anhydr.    Na₂SO₄, and filtered. The filtrate was conc. in vacuo. The residue    was purified by silica gel column chromatography with    EtOAc:petroleum ether (0-10%) to afford the title compound.-   Step F—Ethyl    3,3-dicyano-2-methyl-2-(5-(trifluoromethyl)pyrazin-2-yl)propanoate:    To a flask, under an inert atmosphere of nitrogen, was added ethyl    2-bromo-2-(5-(trifluoromethyl)pyrazin-2-yl)propanoate (270 mg, 0.83    mmol), malononitrile (109 mg, 1.65 mmol), potassium carbonate (114    mg, 0.83 mmol) and DMSO (13 mL). The resulting mixture was stirred    for 2 h at RT. The reaction mixture was quenched by the addition of    water, extracted with EtOAc (3×). The organic layer was washed with    brine, dried over anhydr. Na₂SO₄, and filtered. The filtrate was    conc. in vacuo. The residue was purified by silica gel column    chromatography with EtOAc:petroleum ether (0-20%) to afford the    racemic title compound 1-19. The racemic material was resolved using    Chiral-Prep-HPLC (Chiralpak IA) to afford isomers I-17A (faster    eluting) and I-17B (slower eluting). ¹H NMR (400 MHz, DMSO-d₆) δ    9.32 (s, 1H), 9.23 (s, 1H), 5.88 (s, 1H), 4.25 (q, J=7.2 Hz, 2H),    1.96 (s, 3H), 1.18 (t, J=7.2 Hz, 3H); m/z=311 [M−1]⁻.

Intermediate 18 Ethyl3,3-dicyano-2-methyl-2-(5-(trifluoromethyl)pyrimidin-2-yl)propanoate

-   Step    A—N-(3-(dimethylamino)-2-(trifluoromethyl)allylidene)-N-methylmethanaminium    hexafluorophosphate(V): In a flask containing    3,3,3-trifluoropropanoic acid (7.4 g, 57.8 mmol) and DMF (37 mL) at    70° C. phosphoryl trichloride (26.6 g, 173 4 mmol) was added    dropwise over 1 h. The resulting mixture was stirred at 70° C. for    1.5 h before the mixture was cooled to RT. The reaction mixture and    a 5 N solution of NaOH (100 mL) were added concurrently into a    mixture of 60% hydrogen hexafluorophosphate(V) (15.5 g, 63 7 mmol),    a 5 N NaOH (18.5 mL) and water (67 mL) at a temperature below 10° C.    The resulting mixture was aged for 1 h, filtered and washed with    water. The filter cake was dried in vacuo below 40° C. to afford the    title compound.-   Step B—Ethyl 3-ethoxy-3-imino-2-methylpropanoate hydrochloride: In a    flask containing ethyl 2-cyanopropanoate (10 g, 79 mmol) and EtOH    (100 mL) at 0° C., was bubbled HCl (gas) for 30 min and the mixture    was stirred at 0° C. for 4 h. The reaction mixture was conc. in    vacuo at RT to afford the title compound.-   Step C—Ethyl 3-amino-3-imino-2-methylpropanoate: In a flask    containing ethyl 3-ethoxy-3-imino-2-methylpropanoate hydrochloride    (7.0 g, 33 4 mmol) and EtOH (35 mL) at 0° C., was added a solution    of ammonia in EtOH (22 mL, 3.34 N). The resulting mixture was    stirred at 0° C. for 3 h then stirred for 16 h at RT. The reaction    mixture was conc. in vacuo at RT to afford the title compound.-   Step D—Ethyl 2-(5-(trifluoromethyl)pyrimidin-2-yl)propanoate: In a    flask containing ethyl 3-amino-3-imino-2-methylpropanoate (2.0 g,    13.87 mmol),    N-(3-(dimethylamino)-2-(trifluoromethyl)allylidene)-N-methylmethanaminium    hexafluorophosphate(V) (4.7 g, 13.8 mmol) and acetonitrile (40 mL)    was added triethylamine (2.81 g, 27.7 mmol). The resulting mixture    was stirred at RT for 16 h. The reaction mixture was diluted with    EtOAc, washed with brine (2×), the organic layer was dried over    anhydr. Na₂SO₄, and filtered. The filtrate was conc. in vacuo. The    residue was purified by silica gel column chromatography with    EtOAc:petroleum ether (5-10%) to afford the title compound.-   Step E—Ethyl    2-bromo-2-(5-(trifluoromethyl)pyrimidin-2-yl)propanoate: A flask,    under an inert atmosphere of nitrogen, was charged with ethyl    2-(5-(trifluoromethyl)pyrimidin-2-yl)propanoate (1.0 g, 4.03 mmol)    and THF (20 mL). To this was added lithium bis(trimethylsilyl)amide    (4.83 mL, 4.83 mmol) dropwise at 0° C. The resulting mixture was    stirred at RT for 30 min. Then the mixture was cooled to 0° C. and a    solution of 1-bromopyrrolidine-2,5-dione (1.0 g, 5.64 mmol) in THF    (10 mL) was added in one portion. The resulting mixture was stirred    at RT for 1 h. The reaction mixture was quenched by the addition of    sat. aq. NH₄Cl. The mixture was extracted with EtOAc (3×). The    organic layer was washed with brine (2×), dried over anhydr. Na₂SO₄,    and filtered. The filtrate was conc. in vacuo. The residue was    purified by silica gel column chromatography with EtOAc:petroleum    ether (5-10%) to afford the title compound.-   Step F—Ethyl    3,3-dicyano-2-methyl-2-(5-(trifluoromethyl)pyrimidin-2-yl)propanoate:    To a flask containing ethyl    2-bromo-2-(5-(trifluoromethyl)pyrimidin-2-yl)propanoate (500 mg,    1.53 mmol), malononitrile (202 mg, 3.06 mmol), and DMSO (15 mL) was    added potassium carbonate (215 mg, 1.56 mmol) in portions at RT    during 1 h. The resulting mixture was stirred for 2 h at RT then    quenched by the addition of sat. aq. NH₄Cl. The mixture was    extracted with EtOAc (3×). The organic layer was washed with brine,    dried over anhydr. Na₂SO₄, and filtered. The filtrate was conc. in    vacuo. The residue was purified by silica gel column chromatography    with EtOAc:petroleum ether (5-20%) to afford the title compound. ¹H    NMR (CDCl₃, 400 MHz): δ 9.07 (s, 2H), 5.02 (s, 1H), 4.31 (q, J=7.2    Hz, 2H), 2.08 (s, 3H), 1.28 (d, J=7.2 Hz, 3H); m/z=311 [M−1]⁻.

Intermediate 19, 19A and 19BEthyl-2-(dicyanomethyl))-2-methylbut-3-ynoate and the S and R IsomersThereof

To a flask containing anhydr. LiCl (25.8 mg, 0.609 mmol) in THF (1 mL),was added a solution of ethynylmagnesium bromide (1.3 mL, 0.64 mmol,0.5M in THF). The reaction was stirred at RT for 0.5 h. The resultingsolution was then quickly added dropwise via syringe to a solution ofethyl 3,3-dicyano-2-methylprop-2-enoate (prepared according to Hagiwareet. al. Synthesis 1974, 9, 669) (0.609 mL, 0.609 mmol, 1M solution inbenzene) in THF (22.5 mL) at −10° C. The reaction was stirred for 10 minthen quenched with sat. aq. NH₄Cl and diluted with water and EtOAc. Thelayers were separated and the organic layer was dried over anhydr.Na₂SO₄, and conc. in vacuo to dryness. The residue was purified bysilica gel chromatography using an EtOAc:hexanes gradient to afford theracemic title product 1-19. The racemic material was resolved usingchiral SFC (OJ-H column) to afford isomers I-19A (faster eluting) andI-19B (slower eluting). ¹H NMR (500 MHz, CDCl₃): δ 4.34 (2H, q, J=7.2Hz), 4.31 (1H, s), 2.66 (1H, s), 1.80 (3H, s), 1.35 (3H, t, J=7.1 Hz).

Intermediate 20, 20A and 20B Ethyl3,3-dicyano-2-(5-(difluoromethyl)pyridin-2-yl)-2-methylpropanoate andthe S and R Isomers Thereof

To a 3-necked flask, under an inert atmosphere of nitrogen, containing asolution of n-butyllithium (1.5 mL, 3.65 mmol) in toluene (25 mL), wasadded 2-bromo-5-(difluoromethyl)pyridine (760 mg, 3.65 mmol) in toluene(5 mL) dropwise at −78° C. After 30 min, ethyl3,3-dicyano-2-methylprop-2-enoate (prepared according to Hagiware et.al. Synthesis 1974, 9, 669) (500 mg, 3.05 mmol) in THF (2 mL) was addedin one portion at −78° C. The reaction was stirred for 1 h at −78° C.,then quenched with sat. aq. NH₄Cl and diluted with water and EtOAc. Thelayers were separated and the organic layer was dried over anhydr.Na₂SO₄, and conc. in vacuo to dryness. The residue was purified bysilica gel chromatography using an EtOAc/petroleum ether (10%-15%)gradient. The crude product was purified with C18 column withacetonitrile/water with 0.05% ammonium bicarbonate (30%-70%) to affordthe racemic title product 20. The racemic material was resolved usingChiral-Prep-HPLC (Chiralpak IA) to afford isomers I-20A (faster eluting)and I-20B (slower eluting). ¹H NMR (300 MHz, CDCl₃): δ 8.73 (s, 1H),7.95 (d, J=8.4 Hz, 1H), 7.63 (d, J=8.4 Hz, 1H), 6.74 (t, J=55.5 Hz, 1H),5.21 (s, 1H), 4.24 (q, J=7.2 Hz, 2H), 2.03 (s, 3H), 1.25 (t, J=7.2 Hz,3H); m/z=292 [M−1]⁻.

Using a similar procedure described for the synthesis of intermediate 19and 20, the following compounds in Table 3 were prepared using eithercommercial starting reagents or from compounds known in the literature.

TABLE 3

Chiral Resolution Int. Column R₃ m/z (M + H) I-21A and 21B CHIRALPAK AS

284   I-22A and 22B CHIRALPAK IA

243.9 I-23 Racemic

308   I-24A and 24B CHIRALPAK AD

262.2 I-25 Racemic

326.9

Intermediate 26, 26A and 26B Ethyl3,3-dicyano-2-(1-isopropyl-1H-1,2,3-triazol-4-yl)-2-methylpropanoate andthe S and R Isomers Thereof

A flask, under an inert atmosphere of nitrogen, was charged withethyl-2-(dicyanomethyl))-2-methylbut-3-ynoate 1-19 (2 g, 10.32 mmol),bromotris(triphenylphosphine)copper(I) (0.192 g, 0.206 mmol) and DMSO(20 mL). To this was added 2-azidopropane (1.27 mL, 12 3 mmol) and thereaction was stirred at 50° C. for 18 h. The reaction mixture wasdiluted with EtOAc, and quenched by the addition of water. The mixturewas extracted with EtOAc (3×). The organic layer was washed with brine(2×), dried over anhydr. magnesium sulfate, and filtered. The filtratewas conc. in vacuo. The residue was purified by silica gel columnchromatography with EtOAc:hexane (0-50%) to afford the racemic titlecompound 1-26. The racemic material was resolved using chiral SFC(CHIRALCEL ID) to afford isomers I-26A (faster eluting) and I-26B(slower eluting).¹H NMR (CHCl₃, 400 MHz): δ 7.66 (1 H, s), 5.01 (1 H,s), 4.88-4.83 (1 H, m), 4.36-4.30 (2 H, m), 1.99 (3 H, s), 1.64 (6 H, d,J=6.8 Hz), 1.34 (3 H, t, J=7.1 Hz),). m/z=276.2 [M+H].

Intermediate 27, 27A and 27B and the S and R Isomers Thereof Methyl2-cyclopropyl-2-(dicyanomethyl)but-3-ynoate

-   Step A—Methyl 3,3-dicyano-2-cyclopropylacrylate: A mixture of methyl    2-cyclopropyl-2-oxoacetate (prepared similarly to: Russian Chemical    Bulletin 2007, 56, 1515-1521) (800 mg, 6.24 mmol) and malononitrile    (516 mg, 7.80 mmol) was stirred for 2-3 min. A solution of    beta-alanine (27.8 mg, 0.312 mmol) in water (540 μl) was added in    small portions over ˜5 min period. The reaction was cooled in an    ice-bath and EtOH (350 μl) was added. The reaction was stirred at RT    for 24 h. The reaction was diluted with water and extracted with    ethyl ether. The ether layer was back extracted with water (2×). The    organic layer was further diluted with EtOAc and dried over anhydr.    Na₂SO₄. The combined organic layers were purified by silica gel    column chromatography with EtOAc:hexanes (0-30%) to give the title    compound.-   Step B—Methyl 2-cyclopropyl-2-(dicyanomethyl)but-3-ynoate: To a    flask containing anhydr. LiCl (144 mg, 3.41 mmol) in THF (2 mL) was    added a solution of ethynylmagnesium bromide (6.8 mL, 3.41 mmol, 0.5    M in THF). The reaction was stirred at RT for 30 min. The resulting    solution was cooled to −30° C. A solution of Methyl    3,3-dicyano-2-cyclopropylacrylate (0.500 g, 2.84 mmol) in THF (5 mL)    was added. The reaction was stirred for 1 h in then raised to RT    slowly. The mixture was quenched with sat. aq. NH₄Cl, and then    diluted with water and EtOAc. The layers were separated and the    organic layer was dried over anhydr. Na₂SO₄ and conc. in vacuo.    Purification by silica gel column chromatography with EtOAc:hexanes    (0-30%) gave the racemic title compound 1-27. The racemic material    was resolved using chiral SFC (CHIRALCEL OJ-H) to afford isomers    I-27A (faster eluting) and I-27B (slower eluting). ¹H NMR (500 MHz,    CDCl₃): δ 4.41 (1 H, s), 3.93 (3 H, s), 2.63 (1 H, s), 1.31-1.24 (1    H, m), 1.03-0.96 (1 H, m), 0.92-0.79 (2 H, m), 0.77-0.67 (1 H, m).

Intermediate 28, 28A and 28B and the S and R Isomers Thereof Methyl3,3-dicyano-2-cyclopropyl-2-(5-(trifluoromethyl)pyridin-2-yl)propanoate

To a flask, under an inert atmosphere of nitrogen, was added toluene(300 mL) and n-butyl-lithium (14.8 mL, 36.9 mmol, 2.5M in hexane).2-Bromo-5-(trifluoromethyl)pyridine (8.34 g, 36.9 mmol) in toluene (15mL) was added dropwise with stirring at −78° C. The resulting mixturewas stirred for 45 min at −78° C. To this was added Methyl3,3-dicyano-2-cyclopropylacrylate (5 g, 28 mmol) in THF (20 mL). Theresulting mixture was stirred for 0.5 h at −78° C. The reaction mixturewas quenched by the addition of sat. aq. NH₄Cl. The mixture wasextracted with EtOAc (3×). The organic layer was washed with brine,dried over anhydr. Na₂SO₄, and filtered. The filtrate was conc. invacuo. The residue was purified by silica gel column chromatography withEtOAc:petroleum ether (5-30%). The major component was further purifiedby RP-HPLC with acetonitrile:water (0.3% ammonium bicarbonate) to affordthe racemic title compound 1-28. The racemic material was resolved usingchiral SFC (CHIRALPAK AD-H) to afford isomers I-28A (faster eluting) andI-28B (slower eluting). ¹H NMR (300 MHz, CDCl₃) δ 8.86 (s, 1H), 8.05(dd, J=1.8, 8.4 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 5.06 (s, 1H), 3.78 (s,3H), 1.65-1.55 (m, 1H), 1.08-0.84 (m, 3H), 0.63-0.54 (m, 1H); m/z=322[M−1]⁻.

Using a similar procedure to that described in Intermediates 27 & 28,the following compounds in Table 4 were prepared using either commercialstarting reagents or from compounds known in the literature.

TABLE 4

Chiral Resolution m/z Int. Column R₃ R (M + H) I-29A and 29B CH1RALPAKAS

Et 285.0 [M − 1]⁻ I-30A and 30B CHIRALPAK IC

Et 301.2 [M − 1]⁻ I-31A and 31B CHIRALCEL OJ

Me 305   [M − 1]⁻ I-32A and 32B CHIRALCEL OJ

Me 289   [M − 1]⁻ I-33A and 33B CHIRALCEL OJ

Me 321   [M − 1]⁻ I-34A and 34B CHIRALCEL OJ

Me 274   I-35A and 35B CHIRALPAK AD

Me 290.1 I-36A and 36B CHIRALCEL OJ

Me 286   I-37 Racemic

Me 270.0 I-38 Racemic

Me 304   [M − 1]⁻ I-39A and 39B CHIRALPAK AD

Me 274.2 I-40 Racemic

Me 268.9 [M − 1]⁻ I-44 Racemic

Me 322.9 [M − 1]⁻

Intermediate 41 Diethyl 2-cyclopropyl-2-(dicyanomethyl)malonate

A THF (45.0 mL) solution of diethyl 2-(dicyanomethylene)malonate(prepared analogously to Sentman et. al. J. Org. Chem. 1982, 47, 4577)(4.50 mL, 4.50 mmol, 1M solution in benzene) was cooled to 0° C. andcyclopropylmagnesium bromide (9.00 mL, 4.50 mmol) and lithium chloride(0.191 g, 4.50 mmol) were added. The reaction was stirred at 0° C. for 2hours and then warmed to RT while stirring for an additional 2 h. Thereaction was diluted with EtOAc and quenched with sat. NH₄Cl. The layerswere separated and the organic layer was dried over anhydr. MgSO₄,filtered, and conc. in vacuo to dryness. Purification by silica gelcolumn chromatography using a EtOAc:hexanes gradient afforded the titlecompound. ¹H NMR (500 MHz, CDCl₃): δ 4.41 (1H, s), 4.38-4.26 (4H, m),1.52-1.45 (1H, m), 1.33 (6H, t, J=7.1 Hz), 0.86-0.79 (2H, m), 0.71-0.66(2H, m).

Intermediate 42 Diethyl 2-(dicyanomethyl)-2-methylmalonate

Using a similar procedure as described in intermediate 41, the followingintermediate was prepared. ¹H NMR (500 MHz, CDCl₃): δ 4.55 (1 H, s),4.28-4.39 (4 H, m), 1.82 (3 H, s), 1.34(6 H, t, J=7.12 Hz).

Intermediate 43, 43A and 43B and the S and R Isomers Thereof Ethyl2-(5-chloropyrimidin-2-yl)-3,3-dicyano-2-cyclopropylpropanoate

-   Step A—Ethyl 2-cyano-2-cyclopropylacetate: To a flask, under an    inert atmosphere of nitrogen, was added diethyl carbonate (29.1 g,    247 mmol), sodium hydride (15.3 g, 382 mmol), and toluene (80 mL).    To this was added 2-cyclopropylacetonitrile (10 g, 123 mmol) in    toluene (40 mL) dropwise with stirring at reflux, over a period of    30 min. The resulting mixture was stirred for 2 h at reflux, then    cooled to 0° C. To this was added acetic acid (40 mL) dropwise at 0°    C., followed by water (100 mL). The mixture was extracted with EtOAc    (3×). The organic layer was washed with brine, dried over anhydr.    Na₂SO₄, and filtered. The filtrate was conc. in vacuo and    distillation at reduced pressure (86˜90° C. at ˜10 mmHg) to afford    the title compound.-   Step B—Ethyl 2-cyclopropyl-3-imino-3-methoxypropanoate    hydrochloride: In a flask containing ethyl    2-cyano-2-cyclopropylacetate (10.6 g, 69 2 mmol) and EtOH (100 mL)    at 0° C. was introduced gaseous hydrogen chloride for 4 h. The    reaction mixture was conc. in vacuo at RT to afford the title    compound.-   Step C—Ethyl 3-amino-2-cyclopropyl-3-iminopropanoate: In a flask    containing ethyl 2-cyclopropyl-3-ethoxy-3-iminopropanoate    hydrochloride (15.6 g, 66 2 mmol) and EtOH (50 mL) at 0° C. was    added ammonia (70 mL, 206 mmol, 3 N). The resulting mixture was    stirred for 3 h at 0° C., then stirred for 16 h at RT. The reaction    mixture was conc. in vacuo at RT to afford the title compound.-   Step D—Ethyl 2-(5-chloropyrimidin-2-yl)-2-cyclopropylacetate: To a    flask, under an inert atmosphere of nitrogen, was added sodium (2.7    g, 117 mmol) and EtOH (200 mL), the resulting mixture was stirred    for 1 h at RT. To this was added ethyl    3-amino-2-cyclopropyl-3-iminopropanoate (15.2 g, 62.5 mmol). The    resulting mixture was stirred for 10 min at RT then cooled to 5° C.    N-(2-chloro-3-(dimethylamino)allylidene)-N-methylmethanaminium    hexafluorophosphate(V) (8.7 g, 28.4 mmol) (prepared according to    Davis et. al. Org. Synth. 2003, 80, 200) was then added in portions    over 45 min. The resulting mixture was stirred 2 h at RT. The    reaction mixture was quenched by the addition of sat. aq. NH₄Cl. The    mixture was extracted with EtOAc (3×). The organic layer was washed    with brine, dried over anhydr. Na₂SO₄, and filtered. The filtrate    was conc. in vacuo. The residue was purified by silica gel column    chromatography with EtOAc:petroleum ether (5-10%) to afford the    title compound.-   Step E—Ethyl    2-bromo-2-(5-chloropyrimidin-2-yl)-2-cyclopropylacetate: A flask,    under an inert atmosphere of nitrogen, was charged with ethyl    2-(5-chloropyrimidin-2-yl)-2-cyclopropylacetate (300 mg, 1.25 mmol)    and THF (20 mL) and cooled to 0° C. To this was added lithium    bis(trimethylsilyl)amide (1.50 mL, 1.50 mmol, 1M in THF) dropwise    with stirring at 0° C. The resulting mixture was stirred for 1 h at    0° C. then NBS (333 mg, 1.87 mmol) was added and the mixture was    allowed to stir for 2 h at RT. The reaction mixture was quenched by    the addition of sat. aq. NH₄Cl. The mixture was extracted with EtOAc    (3×). The organic layer was washed with brine, dried over anhydr.    Na₂SO₄, and filtered. The filtrate was conc. in vacuo to dryness.    The residue was purified by silica gel column chromatography with    EtOAc:petroleum ether (0-10%) to afford the title compound.-   Step F—Ethyl    2-(5-chloropyrimidin-2-yl)-3,3-dicyano-2-cyclopropylpropanoate: To a    flask containing ethyl    2-bromo-2-(5-chloropyrimidin-2-yl)-2-cyclopropylacetate (250 mg,    0.78 mmol), malononitrile (258 mg, 3.91 mmol), and DMSO (10 mL) was    added potassium carbonate (216 mg, 1.57 mmol) in portions at RT. The    resulting mixture was stirred for 16 h at RT. The reaction mixture    was quenched by the addition of sat. aq. NH₄Cl. The mixture was    extracted with EtOAc (3×). The organic layer was washed with brine,    dried over anhydr. Na₂SO₄, and filtered. The filtrate was conc. in    vacuo to dryness. The residue was purified by silica gel column    chromatography with EtOAc:petroleum ether (5-20%) to afford the    racemic title compound 1-43. The racemic material was resolved using    Chiral-Prep-HPLC (CHIRALCEL OJ-H) to afford isomers I-43A (faster    eluting) and I-43B (slower eluting). ¹H NMR (400 MHz, CDCl₃) δ 8.76    (s, 2H), 4.78 (s, 1H), 4.36 (q, J=7.2 Hz, 2H), 1.81-1.75 (m, 1H),    1.31 (t, J=7.2 Hz, 3H), 0.72-0.75 (m, 2H), 0.57-0.44 (m, 2H);    m/z=305 [M+1]⁺

Intermediate A18-(4,4,4-Trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazine-6-carboximidamide

-   Step A—(4,4,4-Trifluorobutyl)zinc(II) bromide: Into a flask, under    an inert atmosphere of nitrogen, was placed    1,1,1-trifluoro-4-iodobutane (6.7 g, 28 mmol), zinc metal (3.7 g, 56    mmol) and DMA (10 mL). This was followed by the dropwise addition of    a solution of iodine (0.33 g, 1.3 mmol) in DMA (0.5 mL). The    resulting mixture was stirred for 3 h at 80° C. The reaction was    cooled and directly used in the next step.-   Step    B—6-Bromo-8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazine:    Into a flask, under an inert atmosphere of nitrogen, was placed    6,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazine (6.0 g, 22 mmol),    Pd(PPh₃)₂Cl₂ (0.91 g, 1.3 mmol) and THF (80 mL). The resulting    mixture was allowed to stir for 1 h at RT. The intermediate from    Step A (11 mL, 28 mmol) was added and the resulting solution was    stirred for 16 h at RT. The reaction was quenched by the addition of    sat. aq. NH₄Cl. The resulting solution was extracted with EtOAc (3×)    and the organic layers were combined, washed with brine, dried over    anhydr. Na₂SO₄, and filtered. The filtrate was conc. in vacuo to    dryness. The residue purified by silica gel chromatography with    EtOAc:petroleum ether (0-20%) to afford the title compound.-   Step    C—8-(4,4,4-Trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazine-6-carbonitrile:    Into a flask, under an inert atmosphere of nitrogen, was placed the    intermediate from Step B (2.3 g, 7.4 mmol), zinc cyanide (1.14 g,    9.67 mmol), dppf (0.83 g, 1.5 mmol), Pd₂(dba)₃ (0.77 g, 0.74 mmol),    zinc metal (0.243 g, 3.72 mmol) and DMF (25 mL). The resulting    mixture was warmed at 120° C. for 1 h. The reaction was cooled to RT    and quenched by the addition of water and EtOAc. The precipitate was    filtered through CELITE and the filtrate was extracted with EtOAc    (3×). The organic layers were combined, dried over anhydr. Na₂SO₄,    filtered and the filtrate was conc. in vacuo to dryness. The residue    was purified by silica gel chromatography with EtOAc:petroleum ether    (5-25%) to afford the title compound.-   Step    D—8-(4,4,4-Trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazine-6-carboximidamide:    Into a flask, under an inert atmosphere of nitrogen, was placed    NH₄Cl (3.60 g, 67 3 mmol) and toluene (60 mL). This was followed by    the dropwise addition of trimethyl aluminum (25.4 mL, 50.8 mmol, 2.0    M in toluene) with stirring at 0° C. The reaction was slowly warmed    to RT over 1.5 h. To this was added a solution of the intermediate    from Step C (1.62 g, 6.35 mmol) in toluene (10 mL). The resulting    mixture was stirring for an additional 2 h at 100° C. The reaction    mixture was cooled to 0° C., then quenched by the addition of    MeOH:CH₂Cl₂ (1:1). The solid was filtered through CELITE and washed    with MeOH:DCM (1:1). The combined filtrate was conc. in vacuo to    dryness. The pH value was adjusted to 10 with NaOH (1 N). The    resulting solution was extracted with EtOAc (3×), and the organic    layers were combined, dried over anhydr. Na₂SO₄, filtered and the    filtrate was conc. in vacuo to dryness to afford the title compound.    ¹H NMR (300 MHz, CDCl₃): δ 9.41 (1H, s), 8.50 (1H, s), 5.82 (3H,    brs), 3.41 (2H, t, J=6.9 Hz), 2.34-2.21 (4H, m). m/z=309.0 (M+H).

Intermediate A28-(3,3,4,4,4-Pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazine-6-carboximidamide

-   Step A—(3,3,4,4,4-Pentafluorobutyl)zinc(II) bromide: Into a flask,    under an inert atmosphere of nitrogen, was placed    1,1,1,2,2-pentafluoro-4-iodobutane (21.7 g, 79 mmol), zinc metal    (8.4 g, 128 mmol) and DMA (60 mL). This was followed by the dropwise    addition of a solution of iodine (0.77 g, 3.05 mmol) in DMA (4 mL).    The resulting mixture was stirred for 3 h at 80° C. The reaction was    cooled and directly used in the next step.-   Step B—5-Chloro-3-(3,3,4,4,4-pentafluorobutyl)pyrazin-2-amine: In a    flask, under an inert atmosphere of argon, was added    3,5-dichloropyrazin-2-amine (10.0 g, 61.0 mmol) and Pd(PPh₃)₂Cl₂    (4.3 g, 6.1 mmol). The resulting mixture was allowed to stir for 1 h    at RT. The intermediate from Step A (65 mL, 79 mmol) was added and    the resulting solution was warmed at 45° C. for 3 h. The reaction    was then quenched by the addition of sat. aq. NH₄Cl. The resulting    solution was extracted with EtOAc (3×), and the organic layers    combined, washed with brine, dried over anhydr. Na₂SO₄, and    filtered. The filtrate was conc. in vacuo to dryness. The residue    was purified RP-HPLC with acetonitrile:water (0.2% TFA) to afford    the title compound.-   Step    C—N′-(5-Chloro-3-(3,3,4,4,4-pentafluorobutyl)pyrazin-2-yl)-N,N-dimethylformimidamide:    In a flask was placed the intermediate from Step B (3.0 g, 11 mmol),    DMF-DMA (1.75 mL, 13.1 mmol) and EtOH (30 mL). The resulting mixture    was warmed at 90° C. for 2 h. The resulting solution was conc. in    vacuo to afford the title compound, which was used without further    purification.

StepD—N-(5-Chloro-3-(3,3,4,4,4-pentafluorobutyl)pyrazin-2-yl)-N′-hydroxyformimidamide:In a flask was placed the intermediate from Step C (3.5 g, 11 mmol),hydroxylamine hydrochloride (1.1 g, 15 mmol) and MeOH (20 mL). Theresulting mixture was stirred at RT for 18 h. The precipitate wasfiltered, and the filtrate was conc. in vacuo. The residue was purifiedby silica gel chromatography with MeOH:DCM (10%) to afford the titlecompound.

-   Step    E—6-Chloro-8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazine:    In a flask, under an inert atmosphere of nitrogen, was placed the    intermediate from Step D (2.5 g, 7.9 mmol), 2,2,2-trifluoroacetic    anhydride (8.1 mL, 57 mmol) and toluene (12.5 mL). The resulting    mixture was warmed at 90° C. for 2 h. The reaction was conc. in    vacuo. Then sat. aq. NaHCO₃ was added to adjust the pH to 8. The    resulting mixture was extracted with EtOAc (3×). The organic layers    were combined, washed with brine, dried over anhydr. Na₂SO₄,    filtered, and conc. in vacuo. The residue was purified by silica gel    chromatography with EtOAc:petroleum ether (0-30%) to afford the    title compound.-   Step    F—8-(3,3,4,4,4-Pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazine-6-carbonitrile:    Into a flask, under an inert atmosphere of nitrogen, was placed the    intermediate from Step E (1.0 g, 3.3 mmol), Pd₂(dba)₃ (0.34 g, 0.33    mmol), dppf (0.37 g, 0.67 mmol), zinc cyanide (0.51 g, 4.32 mmol),    zinc metal (0.11 g, 1.7 mmol) and DMF (15 mL). The resulting mixture    was warmed at 120° C. for 5 h. The reaction was cooled to RT,    quenched by the addition of brine and EtOAc and the precipitate was    filtered. The filtrate was extracted with EtOAc (3×). The organic    layers were combined, washed with brine, dried over anhydr. Na₂SO₄,    filtered, and conc. in vacuo. The residue was purified by silica gel    chromatography with EtOAc:petroleum ether (0-20%) to afford the    title compound.-   Step    G—8-(3,3,4,4,4-Pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazine-6-carboximidamide:    In a flask, under an inert atmosphere of nitrogen, was placed NH₄Cl    (1.46 g, 27.3 mmol) and toluene (20 mL). This was followed by the    dropwise addition of trimethyl aluminum (14 mL, 2.0 M in toluene) at    0° C. The resulting mixture was stirred for 1 h at RT. To this was    added the intermediate from Step F (750 mg, 2.58 mmol). The    resulting mixture was warmed at 100° C. for 4 h. The reaction    mixture was cooled to 0° C., and quenched by the addition of    MeOH:DCM (1:1). The solid was filtered through CELITE. The eluent    was conc. in vacuo. The residue was dissolved in EtOAc. The pH value    of the solution was adjusted to pH 10 with NaOH (1 N). The resulting    solution was extracted with EtOAc (3×), and the organic layers were    combined, dried over anhydr. Na₂SO₄, filtered and the filtrate was    conc. in vacuo to dryness to afford the title compound. ¹H NMR (300    MHz, DMSO-d₆): δ 9.44 (1H, s), 8.80 (1H, s), 6.94 (2H, brs), 3.51    (2H, t, J=7.8 Hz), 3.08-2.90 (m, 2H). m/z=309.0 (M+H).

Intermediate A3

-   Step A—Propylzinc(II) iodide: Into a flask, under an inert    atmosphere of nitrogen, was placed 1-iodopropane (10.9 g, 64.0    mmol), zinc metal (8.4 g, 128 mmol) and N,N-dimethylpropionamide (28    mL). This was followed by the dropwise addition of a solution of    iodine (0.1 g, 0.43 mmol) in N,N-dimethylpropionamide (2 mL) at    0° C. The resulting mixture was stirred for 3 h at 80° C. The    reaction was cooled and directly used in the next step.-   Step B—5-chloro-3-propylpyrazin-2-amine: In a flask, under an inert    atmosphere of argon, was added 3,5-dichloropyrazin-2-amine (7.0 g,    42 7 mmol), bis(triphenylphosphine)palladium(II) dichloride (3.0 g,    4.27 mmol) and THF (240 mL). The resulting mixture was allowed to    stir for 1 h at RT. The intermediate from Step A (30 mL, 64 mmol)    was added and the resulting solution was warmed at 35° C. for 2    days. The reaction was then quenched by the addition of brine. The    resulting solution was extracted with EtOAc (3×) and the organic    layers combined, washed with brine, dried over anhydr. Na₂SO₄, and    filtered. The residue was purified by silica gel chromatography with    EtOAc:petroleum ether (5-20%) to afford the title compound.-   Step C—N′-(5-chloro-3-propylpyrazin-2-yl)-N,N-dimethylacetimidamide:    In a flask was placed 5-chloro-3-propylpyrazin-2-amine (6.0 g, 35.0    mmol), 1,1-dimethoxy-N,N-dimethylethanamine (5.6 g, 42.0 mmol) and    ethanol (60 mL). The resulting mixture was stirred for 3 h at 90° C.    The ethanol was removed in vacuo. The residue was diluted with    EtOAc, washed with brine, dried over anhydr. Na₂SO₄, filtered, and    conc. in vacuo. The residue was purified by silica gel    chromatography with EtOAc:petroleum ether (5-20%) to afford the    title compound.-   Step D—N-(5-chloro-3-propylpyrazin-2-yl)-N′-hydroxyacetimidamide:    Into a flask was placed    N′-(5-chloro-3-propylpyrazin-2-yl)-N,N-dimethylacetimidamide (6.4 g,    26.6 mmol), MeOH (60 mL) and hydroxylamine hydrochloride (2.7 g,    38.3 mmol). The resulting mixture was stirred for 16 h at RT, then    conc. in vacuo to dryness. The residue was purified by silica gel    chromatography with EtOAc:petroleum ether (5-30%) to afford the    title compound.-   Step E—6-chloro-2-methyl-8-propyl-[1,2,4]triazolo[1,5-a]pyrazine:    Into a flask was placed    N′-(5-chloro-3-propylpyrazin-2-yl)-N-hydroxyacetimidamide (6.0 g,    26.2 mmol), toluene (60 mL) and 2,2,2-trifluoroacetic anhydride    (40.2 g, 192 mmol). The resulting mixture was stirred for 2 days at    90° C. The reaction was conc. in vacuo. Then sat. aq. Na₂HCO₃ was    added to adjust the pH to 8. The resulting mixture was extracted    with EtOAc (3×), and the organic layers combined, washed with brine,    dried over anhydr. Na₂SO₄, and filtered. The residue was purified by    silica gel chromatography with EtOAc:petroleum ether (5-30%) to    afford the title compound.-   Step F—Synthesis of    2-methyl-8-propyl-[1,2,4]triazolo[1,5-a]pyrazine-6-carbonitrile: In    a flask, under an inert atmosphere of argon, was added    6-chloro-2-methyl-8-propyl-[1,2,4]triazolo[1,5-a]pyrazine (4.6 g, 21    8 mmol), tris(dibenzylideneacetone)dipalladium-chloroform adduct    (2.3 g, 2.18 mmol), 1,1′-bis(diphenylphosphino)ferrocene (2.4 g,    4.37 mmol), zinc metal (0.7 g, 10.92 mmol), zinc cyanide (3.3 g,    28.40 mmol) and DMA (50 mL). The resulting mixture was stirred for 6    h at 120° C. then cooled to RT and diluted with EtOAc (50 mL), MeOH    (50 mL) and DCM (50 mL). The solid was filtered through CELITE. The    combined filtrate was conc. in vacuo to dryness. The residue was    dissolved in EtOAc, washed with brine, dried over anhydr. Na₂SO₄,    and filtered. The residue was purified by silica gel chromatography    with EtOAc:petroleum ether (15-60%) to afford the title compound.-   Step    G—2-methyl-8-propyl[1,2,4]triazolo[1,5-a]pyrazine-6-carboximidamide:    In a flask, under an inert atmosphere of argon, was added NH₄Cl    (11.0 g, 205 mmol) and toluene (200 mL), the resulting mixture was    cooled to 0° C. and trimethyl aluminum (78 mL, 155 mmol) was added    dropwise. The resulting mixture was stirred for 1 h at RT before    2-methyl-8-propyl-[1,2,4]triazolo[1,5-a]pyrazine-6-carbonitrile (3.9    g, 19.38 mmol) was added. The resulting mixture was stirred for    additional 3 h at 100° C. then cooled to 0° C. and quenched by the    addition of DCM:MeOH in a ratio of 1:1 (200 mL). The precipitate was    removed by filtration through CELITE. The resulting filtrate was    conc. in vacuo. The residue was dissolved in EtOAc. The pH value of    the solution was adjusted to pH 10 with NaOH (1 N). The resulting    solution was extracted with a mixture DCM:MeOH (10:1, 6×), and the    organic layers were combined, dried over anhydr. Na₂SO₄, filtered    and conc. in vacuo to dryness affording the title compound. ¹H NMR    (300 MHz, DMSO-d₆) δ 9.27 (s, 1H), 6.90-6.72 (br, 3H), 3.15 (t,    J=7.2 Hz, 2H), 2.57 (s, 3H), 1.94-1.84 (m, 2H), 0.98 (t, J=7.2 Hz,    3H); m/z=219.2 [M+1]⁺.

Using a similar procedure to that described in Intermediate A1, A2 andA3, the following compounds in Table 5 were prepared using eithercommercial starting reagents or from compounds known in the literature.

TABLE 5

Int. R₁ R₂ m/z (M + H) I-A4 

H 205   I-A5 

H 219.2 I-A6 

H 219.2 I-A7 

H 259.0 I-A8 

H 271.1 I-A9 

H 283.1 I-A10

Me 285.1 I-A11

Me 323.0

Intermediate A12 [1,2,4]Triazolo[1,5-a]pyrazine-6-carboximidamide

-   Step A—[1,2,4]triazolo[1,5-a]pyrazine-6-carbonitrile: Into a flask,    under an inert atmosphere of nitrogen, was placed    6-bromo-[1,2,4]triazolo[1,5-a]pyrazine (1.0 g, 5.02 mmol), Pd₂(dba)₃    (460 mg, 0.50 mmol), dppf (557 mg, 1.00 mmol), zinc cyanide (649 mg,    5.53 mmol), zinc metal (164 mg, 2.51 mmol) and DMA (20 mL). The    resulting mixture was warmed at 100° C. for 4 h. The reaction was    cooled to RT, quenched by the addition of brine and EtOAc and the    precipitate was filtered. The filtrate was extracted with EtOAc    (3×). The organic layers were combined, washed with brine, dried    over anhydr. Na₂SO₄, filtered, and conc. in vacuo. The residue was    purified by silica gel chromatography with EtOAc:petroleum ether    (0-50%) to afford the title compound.-   Step-B—[1,2,4]Triazolo[1,5-a]pyrazine-6-carboximidamide: In a flask,    under an inert atmosphere of nitrogen, was placed    [1,2,4]triazolo[1,5-a]pyrazine-6-carbonitrile (440 mg, 3.03 mmol)    and MeOH (10 mL). This was followed by the addition of NaOMe (30% in    MeOH) (0.626 mL, 3.34 mmol) at RT. The resulting mixture was stirred    for 2 h at RT. To this was added NH₄Cl (178 mg, 3.34 mmol) and AcOH    (1.73 mL, 30.3 mmol). The resulting mixture was warmed at 70° C. for    4 h. The reaction mixture was cooled to RT and was conc. in vacuo to    dryness. The resulting solid was azeotroped with EtOAc and toluene    to afford the title compound.

EXAMPLE 1A(S)-4-Amino-5-(4-fluorophenyl)-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one

Into a vial was placed I-A2 (50 mg, 0.16 mmol), I-1A (44 mg, 0.17 mmol),potassium bicarbonate (33 mg, 0.32 mmol) and t-BuOH (2 mL). Theresulting mixture was warmed at 70° C. for 16 h. The reaction was cooledto RT and quenched by the addition of brine. The resulting solution wasextracted with EtOAc (3×) and the organic layers were combined, driedover anhydr. Na₂SO₄, filtered and the filtrate was conc. in vacuo todryness. The residue was purified by silica gel chromatography usingMeOH:DCM (10%) to afford the title product. ¹H NMR (300 MHz, DMSO-d₆): δ11.26 (1H, brs), 9.44 (1H, s), 8.23 (1H, s), 7.30 (2H, dd, J=5.7, 9.0Hz), 7.19 (2H, dd, J=9.0, 9.0 Hz), 6.66 (2H, brs), 3.55 (2H, t, J=7.8Hz), 3.03-2.88 (2H, m), 1.80 (3H, s); m/z=523.4 (M+H).

EXAMPLE 2A4-Amino-5-cyclopropyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(5-(trifluoromethyl)pyridin-2-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one

Into a vial was placed I-A1 (50 mg, 0.18 mmol), I-28A (59 mg, 0.18mmol), potassium bicarbonate (37 mg, 0.37 mmol), and t-BuOH (3 mL). Theresulting mixture was warmed at 80° C. for 16 h. The reaction was cooledto RT and conc. to remove any volatiles. The residue was purified bysilica gel chromatography using MeOH:DCM (1-3%) to afford the titleproduct. ¹H NMR (300 MHz, CD₃OD): δ 9.62 (1H, s), 8.92 (1H, s), 8.64(1H, s), 8.22 (1H, dd, J=2.4, 8.4 Hz), 8.06 (1H, d, J=8.4 Hz), 3.42 (2H,t, J=7.8 Hz), 2.43-2.22 (4H, m), 2.03-1.98 (1H, m), 0.75-0.59 (4H, m);m/z=564.3 (M+H).

Using essentially the same procedures described in Examples 1 & 2, thefollowing compounds in Table 6 were prepared.

TABLE 6 Chiral MS starting Ex Structure Name (M + 1) material  3A

4-amino-5-(5-chloropyridin-2-yl)-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 540.4 I-9A  4B

4-amino-5-(5-fluoropyridin-2-yl)-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 524.2 I-8B  5B

4-amino-5-(4-chloro-3-fluorophenyl)-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 557.3 I-4B  6A

4-amino-5-cyclopropyl-5-(3,4- difluorophenyl)-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5- a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 567.1 I-32A  7A

4-amino-5-(5-chloropyridin-2-yl)-5- cyclopropyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5- a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 566.3 I-35A  8B

4-amino-5-cyclopropyl-5-(5- fluoropyridin-3-yl)-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5- a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 550.1 I-39B  9A

4-amino-5-(5-fluoropyridin-3-yl)-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 524.1 I-24A 10A

4-amino-5-(4-chlorophenyl)-5-methyl-2- (8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 539.1 I-2A 11B

4-amino-5-methyl-2-(8-(3,3,4,4,4- pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(pyridin-2-yl)-5H- pyrrolo[2,3-d]pyrimidin-6(7H)-one506.3 I-22B 12B

4-amino-5-methyl-2-(8-(3,3,4,4,4- pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-phenyl-5H-pyrrolo[2,3- d]pyrimidin-6(7H)-one 505.0I-11B 13B

4-amino-5-(6-cyclopropylpyridin-3-yl)-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 546.3 I-21B 14B

4-amino-5-(3-fluorophenyl)-5-methyl-2 (8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 523.3 I-7B 15A

4-amino-5-cyclopropyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5- a]pyrazin-6-yl)-5-(5-(trifluoromethyl)pyridin-2-yl)-5H- pyrrolo[2,3-d]pyrimidin-6(7H)-one600.3 I-28A 16B

4-amino-5-(6-(1,1-difluoroethyl)pyridin- 3-yl)-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5- a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (slow eluting) 570.3 CHIRAL PAK IB (Rac-I- 23) 17B

4-amino-5-cyclopropyl-5-(5- methylpyridin-2-yl)-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5- a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (slow eluting) 546.2 CHIRAL PAK IC (Rac-I- 37) 18A

6-(4-amino-5-methyl-6-oxo-2-(8- (3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5- yl)nicotinonitrile 531.3 I-15A 19B

4-amino-5-methyl-5-(5-methylpyridin-2-yl)-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pynizin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 520.2 I-14B 20A

4-amino-5-(1-isopropyl-1H-1,2,3-triazol- 4-yl)-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5- a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 538.1 I-26A 21B

4-amino-5-cyclopropyl-5-(5- methylpyrazin-2-yl)-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5- a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (slow eluting) 547.3 CHIRAL PAK IB (rac-I- 40) 22B

4-amino-5-(5-fluoropyridin-2-yl)-5- methyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 488.3 I-8B 23A

(S)-4-amino-5-(4-fluorophenyl)-5- mclhyl-2-(S-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6- one 487.1 I-1A 24B

4-amino-5-methyl-2-(8-(4,4,4- trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(4- (trifluoromethyl)phenyl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 537.1 I-3B 25B

4-amino-5-methyl-2-(8-(4,4,4- trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(5- (trifluoromethyl)pyridin-2-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 538.4 I-13B 26A

4-amino-5-(5-chloropyridin-2-yl)-5- methyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyriniidin-6(7H)-one 504.1 I-9A 27A

4-amino-5-(5-chloropyridin-2-yl)-5-cyclopropyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 530.3 I-35A 28B

4-amino-5-(4-chloro-3-fluorophenyl)-5-methyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 521.3 I-4B 29A

4-amino-5-(4-chlorophenyl)-5-methyl-2- (8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 503.2 I-2A 30B

4-amino-5-cyclopropyl-5-(4- fluorophenyl)-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 513.4 I-29B 31B

4-amino-5-(4-chlorophenyl)-5- cyclopropyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 529.4 I-30B 32A

4-amino-5-cyclopropyl-5-(3,4- difluorophenyl)-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5- a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 531.3 I-32A 33A

4-amino-5-(4-chloro-3-fluorophenyl)-5-cyclopropyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 547.3 I-31A 34A

4-amino-5-cyclopropyl-5-(5- fluoropyridin-2-yl)-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5- a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 514.1 I-34A 35A

4-amino-5-cyclopropyl-2-(8-(4,4,4- trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(4- (trifluoromethyl)phenyl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 563.0 I-33A 36B

4-amino-5-methyl-5-(pyridin-2-yl)-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3- d]pyrimidin-6(7H)-one 470.2 I-22B 37B

4-amino-5-methyl-5-phenyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5- a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 469.3 I-11B 38B

4-amino-5-(3,4-difluorophenyl)-5- methyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 505.1 I-5B 39A

4-amino-5-cyclopropyl-5-(5- methoxypyridin-2-yl)-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5- a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 526.2 I-36A 40A

4-amino-5-(5-methoxypyridin-2-yl)-5- methyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 500.3 I-10A 41A

4-amino-5-(5-chloropyrimidin-2-yl)-5-cyclopropyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 531.4 I-43A 42B

4-amino-5-(3-chloro-4-fluorophenyl)-5-methyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 521.2 I-6B 43B

4-amino-5-(5-(difluoromethyl)pyridin-2-yl)-5-methyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 520.4 I-20B 44B

4-amino-5-cyclopropyl-5-(5- (difluoromethyl)pyridin-2-yl)-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3- d]pyrimidin-6(7H)-one (slow eluting)546.1 CHIRAL PAK IC (Rac-I- 38) 45B

4-amino-5-(6-(1,1-difluoroethyl)pyridin- 3-yl)-5-methyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5- a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (slow eluting) 534.2 CHIRAL PAK IB (Rac-I- 23) 46B

4-amino-5-methyl-5-(5-methylpyridin-2- yl)-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H- pyrrolo[2,3-d]pynmidin-6(7H)-one484.1 I-14B 47B

4-amino-5-cyclopropyl-5-(5- methylpyridin-2-yl)-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5- a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (slow cluting) 510.4 CHIRAL PAK IC (Rac-I- 37) 48A

6-(4-amino-5-methyl-6-oxo-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5- a]pyrazin-6-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5- yl)nicotinonitrile 495.3 I-15A 49B

4-amino-5-methyl-5-(6-methyl-5- (trifluoromethyl)pyridin-2-yl)-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3- d]pyrimidin-6(7H)-one (slow eluting)552.3 CHIRAL PAK IA (Rac-I- 25) 50B

4-amino-5-methyl-2-(8-(4,4,4- trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(5- (trifluoromethyl)pyrazin-2-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 539.2 I-17B 51B

4-amino-5-methyl-2-(8-(4,4,4- trifluorobutyl)-[1,2,4]triazolo[1,5-d]pyrazin-6-yl)-5-(5- (trifluoromethyl)pyrimidin-2-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (slow eluting) 539.3 LUX CELLU- LOSE-4(Rac I- 18) 52A

(S)-4-amino-5-(4-fluorophenyl)-5-methyl-2-(8-propyl-[1,2,4]triazolo[1,5- a]pyrazin-6-yl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one 419.3 I-1A 53A

4-amino-5-(4-chlorophenyl)-5-methyl-2-(8-propyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)- one 435.2 I-2A 54B

4-amino-5-(5-fluoropyridin-2-yl)-5-methyl-2-(8-propyl-[1,2,4]triazolo[1,5- a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 420.2 I-8B 55B

5-(5-fluoropyridin-2-yl)-4-hydroxy-5-methyl-2-(8-propyl-[1,2,4]triazolo[1,5- a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 453.3 I-4B 56A

4-amino-5-cyclopropyl-2-(8-propyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(5-(trifluoromethyl)pyridin-2-yl)-5H- pyrrolo[2,3-d]pyrimidin-6(7H)-one496.3 I-28A 57A

4-amino-5-(5-chloropyridin-2-yl)-5- cyclopropyl-2-(8-propyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H- pyrrolo[2,3-d]pynmidin-6(7H)-one462.3 I-35A 58A

4-amino-5-cyclopropyl-5-(3,4- difluorophenyl)-2-(8-propyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 463.2 I-32A 59A

4-amino-5-cyclopropyl-5-(5- fluoropyridin-2-yl)-2-(8-propyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 446.1 I-34A 60A

(S)-4-amino-2-(8-butyl- [1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(4-fluorophenyl)-5-methyl-5,7-dihydro-6H- pyrrolo[2,3-d]pyrimidin-6-one433.3 I-1A 61B

4-amino-2-(8-butyl-[1,2,4]triazolo[1,5-d]pyrazin-6-yl)-5-(5-fluoropyridin-2-yl)-5-methyl-5H-pyrrolo[2,3-d]pyrimidin- 6(7H)-one 434.2 I-8B 62B

4-amino-2-(8-butyl-[1,2,4]triazolo[1,5- a]pyrazin-6-yl)-5-(4-chloro-3-fluorophenyl)-5-methyl-5H-pyrrolo[2,3- d]pyrimidin-6(7H)-one 467.2 I-4B63A

4-amino-2-(8-butyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(4-chlorophenyl)-5- methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 449.1 I-2A 64B

4-amino-2-(8-butyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(3,4-difluorophenyl)-5-methyl-5H-pyrrolo[2,3-d]pyrimidin- 6(7H)-one 451.1 I-5B 65A

4-amino-2-(8-butyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-cyclopropyl-5-(3,4- difluorophenyl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 477.4 I-32A 66A

4-amino-2-(8-butyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-cyclopropyl-5-(5- fluoropyridin-2-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 460.3 I-34A 67B

4-amino-2-(8-butyl-[1,2,4]triazolo[1,5- a]pyrazin-6-yl)-5-methyl-5-(5-(trifluoromethyl)pyridin-2-yl)-5H- pyrrolo[2,3-d]pyrimidin-6(7H)-one484.4 I-13B 68A

4-amino-2-(8-butyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(5-chloropyridin-2-yl)- 5-cyclopropyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 476.3 I-35A 69A

4-amino-2-(8-butyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(5-chloropyridin-2-yl)-5-methyl-5H-pyrrolo[2,3-d]pyrimidin- 6(7H)-one 450.2 I-9A 70A

4-amino-2-(8-butyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-cyclopropyl-5-(5- (trifluoromethyl)pyridin-2-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 510.4 I-28A 71B

4-amino-2-(8-butyl-[1,2,4]triazolo[1,5- a]pyrazin-6-yl)-5-methyl-5-(5-methylpyridin-2-yl)-5H-pyrrolo[2,3- d]pyrimidin-6(7H)-one 430.3 I-14B72B

4-amino-2-(8-butyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-cyclopropyl-5-(5- methylpyridin-2-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (slow eluting) 456.4 CHIRAL PAK IC (Rac-I- 37) 73A

(S)-4-amino-5-(4-fluorophenyl)-2-(8-isobutyl-[1,2,4]triazolo[1,5-a]pyrazin-6- yl)-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one 433.3 I-1A 74A

(S)-4-amino-5-(4-fluorophenyl)-5- methyl-2-(8-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6- one 473.3 I-1A 75B

4-amino-5-(4-chloro-3-fluorophenyl)-5-methyl-2-(8-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 507.2 I-4B 76A

4-amino-5-(4-chlorophenyl)-5-methyl-2- (8-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 489.1 I-2A 77B

4-amino-5-methyl-5-(4- (trifluoromethyl)phenyl)-2-(8-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[1,5- a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 523.2 I-3B 78B

4-amino-5-methyl-5-(5- (tritluoromethyl)pyridin-2-yl)-2-(8-(3,3,3-trifluoropropyl)- [1,2,4]triazolo[1,5-d]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 524.1 I-13B 79A

4-amino-5-(5-chloropyridin-2-yl)-5- methyl-2-(8-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 490.3 I-9A 80A

4-amino-5-cyclopropyl-5-(5- (trifluoromethyl)pyridin-2-yl)-2-(8-(3,3,3-trifluoropropyl)- [1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 550.3 I-28A 81B

4-amino-5-(5-fluoropyridin-2-yl)-5- methyl-2-(8-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 474.3 I-8B 82A

4-amino-5-(5-chloropyridin-2-yl)-5-cyclopropyl-2-(8-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 516.3 I-35A 83A

4-amino-5-cyclopropyl-5-(3,4- difluorophenyl)-2-(8-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[1,5- a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 517.0 I-32A 84B

4-amino-5-(3,4-difluorophenyl)-5- methyl-2-(8-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 491.0 I-5B 85B

(S)-4-amino-2-(8-(4-fluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(4-fluorophenyl)-5-methyl-5H-pyrrolo[2,3- d]pyrimidin-6(7H)-one 485.0 I-16B86B

(S)-4-amino-5-(4-fluorophenyl)-2-(8-(3-methoxybenzyl)-[1,2,4]triazolo[1,5- a]pyrazin-6-yl)-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 497.1 I-16B 87B

(S)-4-amino-2-(8-(4-fluorobenzyl)-2-methyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(4-fluorophcnyl)-5-methyl-5H- pyrrolo[2,3-d]pyrimidin-6(7H)-one499.1 I-16B 88B

(S)-4-amino-5-(4-fluorophenyl)-5- methyl-2-(2-methyl-8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5- a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 537.1 I-16B 89B

4-amino-5-(5-fluoropyridin-2-yl)-5- methyl-2-(2-methyl-8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5- a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 538.1 I-8B 90B

4-amino-5-(4-chloro-3-fluorophenyl)-5- methyl-2-(2-methyl-8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5- a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 571.3 I-4B 91A

(S)-4-amino-5-(4-fluorophenyl)-5- methyl-2-(2-methyl-8-propyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6- one 433.3 I-1A 92B

4-amino-5-(5-fluoropyridin-2-yl)-5- methyl-2-(2-methyl-8-propyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 434.3 I-8B 93A

4-amino-5-(4-chlorophenyl)-5-methyl-2-(2-methyl-8-propyl-[1,2,4]triazolo[1,5- a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 449.2 I-2A 94A

2-([1,2,4]triazolo[1,5-a]pyrazin-6-yl)-4-amino-5-(4-chlorophenyl)-5-methyl-5H- pyrrolo[2,3-d]pyrimidin-6(7H)-one393.0 I-2A

EXAMPLE 95B4-Amino-5-(1-cyclopropyl-1H-1,2,3-triazol-4-yl)-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one

-   Step    A—4-Amino-5-ethynyl-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one:    Into a vial was placed I-A2 (100 mg, 0.324 mmol), I-19B (67.9 mg,    0.357 mmol), potassium bicarbonate (39.0 mg, 0.389 mmol) and t-BuOH    (5 mL). The resulting mixture was warmed at 70° C. for 16 h. The    reaction was cooled to RT and quenched by the addition of brine. The    resulting solution was extracted with EtOAc (3×) and the organic    layers were combined, dried over anhydr. Na₂SO₄, filtered and the    filtrate was conc. in vacuo to dryness. The residue was purified by    silica gel chromatography using MeOH:DCM (10%) to afford the title    product.-   Step    B—4-amino-5-(1-cyclopropyl-1H-1,2,3-triazol-4-yl)-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one:    To a flask containing potassium carbonate (306 mg, 2.21 mmol),    copper(II) sulfate (21 mg, 0.13 mmol), cyclopropanamine (63 mg, 1.11    mmol) and MeOH (7.4 mL) at RT was added 1H-imidazole-1-sulfonyl    azide hydrochloride (278 mg, 1.33 mmol) in water (3.7 mL). The    resulting mixture was stirred for 16 h at 70° C. This was followed    by the addition of sodium    (R)-2-((S)-1,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5-dihydrofuran-3-olate    (70 mg, 0.35 mmol) and the intermediate from Step A (100 mg, 0.22    mmol). The resulting mixture was stirred for 16 h at 70° C. The    reaction was then cooled to RT and quenched by the addition of    ammonia (100 mL). The resulting solution was extracted with EtOAc    (3×) and the organic layers combined, washed with ammonia then    brine, dried over anhydr. Na₂SO₄, and filtered. The residue was    purified by silica gel chromatography with EtOAc:petroleum ether    (5-20%). The crude product was purified by Prep-HPLC,    water:acetonitrile (with 0.05% ammonia) to afford the title    compound.¹H NMR (CD₃OD, 300 MHz): δ 9.61 (s, 1H), 8.61 (s, 1H), 7.95    (s, 1H), 3.92-3.85 (m, 1H), 3.65-3.59 (m, 2H), 3.04-2.86 (m, 2H),    1.81 (s, 3H), 1.25-1.19 (m, 4H); m/z=536.3 [M+1]⁺.

EXAMPLE 96B4-amino-5-cyclopropyl-5-(1-cyclopropyl-1H-1,2,3-triazol-4-yl)-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one

Using essentially the same procedures described in Example 95, Example96 was prepared, using intermediate I-A2 and I-27B as starting material.m/z=562.2 [M+1]⁺.

EXAMPLE 97A AND 97B4-Amino-5-methyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one

-   Step A—Ethyl    4-amino-5-methyl-6-oxo-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxylate:    Into a vial was placed 1-42 (312 mg, 1.31 mmol), I-A2 (336 mg, 1.09    mmol), potassium bicarbonate (218 mg, 2.18 mmol) and t-BuOH (5 mL).    The resulting mixture was warmed at 70° C. for 16 h. The reaction    was cooled to RT and quenched by the addition of brine. The    resulting solution was extracted with EtOAc (3×) and the organic    layers were combined, dried over anhydr. Na₂SO₄, filtered and the    filtrate was conc. in vacuo to dryness. The residue was purified by    silica gel chromatography using MeOH:DCM (10%) to afford the title    compound.-   Step    B—4-Amino-5-methyl-6-oxo-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carbohydrazide:    Into a flask was placed the intermediate from Step A (456 mg, 0.91    mmol), MeOH (8 mL) and hydrazine hydrate (228 mg, 4.56 mmol). The    resulting mixture was warmed at 65° C. for 4 h. The reaction was    cooled to RT and conc. to remove any volatiles. The residue was    purified by silica gel chromatography using MeOH:DCM (10%) to afford    the title compound.-   Step    C—N′-Acetyl-4-amino-5-methyl-6-oxo-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo    [1,5-a]pyrazin-6-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carbohydrazide:    Into a vial was placed AcOH (18 μL, 0.32 mmol), DMF (6 mL), HATU    (123 mg, 0.32 mmol) and Et₃N (0.086 mL, 0.62 mmol). After 20 min,    the intermediate from Step B (150 mg, 0.31 mmol) was added. The    resulting mixture was stirred at RT for 16 h. The reaction was    quenched by the addition of brine, and the resulting solution was    extracted with EtOAc (3×). The organic layers were combined, dried    over anhydr. Na₂SO₄, filtered and the filtrate was conc. in vacuo to    dryness. The residue was purified by silica gel chromatography using    MeOH:DCM (10%) to afford the title compound.-   Step    D—4-Amino-5-methyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one:    Into a flask was placed the intermediate from Step C (150 mg, 0.28    mmol) and polyphosphoric acid (2 mL). The resulting mixture was    warmed at 80° C. for 16 h. The reaction was quenched by the addition    of ice water. The pH of the resulting mixture was adjusted to pH 8    with sat. aq. NaHCO₃. The resulting solution was extracted with    EtOAc (3×) and the organic layers were combined, dried over anhydr.    Na₂SO₄, filtered and the filtrate was conc. in vacuo to dryness. The    residue was purified by silica gel chromatography using MeOH:DCM    (10%) to afford the title compound as a racemate. The racemic    material was resolved using chiral SFC (IA column) to afford isomers    Ex-97A (faster eluting) and Ex-97B (slower eluting) of the title    compound. ¹H NMR (400 MHz, CD₃OD): δ 9.68 (1H, s), 8.67 (1H, s),    3.70-3.65 (2H, m), 3.07-2.93 (2H, m), 2.57 (3H, s), 1.98 (3H, s);    m/z=511.1 (M+H).

Using essentially the same procedures described in Example 97, thefollowing compounds in Table 7 were prepared.

TABLE 1 Chiral MS separation Ex. Structure Name (M + 1) conditions  98B

4-amino-5-(5-cyclopropyl- 1,3,4-oxadiazol-2-yl)-5-methyl-2-(8-(3,3,4,4,4- pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6- yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (slow eluting) 537.5 CHIRALPAK IB  99A

4-amino-5-(5-cyclopropyl- 1,3,4-oxadiazol-2-yl)-5- methyl-2-(8-(4,4,4-trifluorobutyl)- [1,2,4]triazolo[1,5-a]pyrazin-6- yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (fast eluting) 501.1 CHIRALPAK IB 100A

4-amino-5-(5- (difluoromethyl)-1,3,4- oxadiazol-2-yl)-5-methyl-2-(8-(4,4,4-trifluorobutyl)- [1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3- d]pyrimidin-6(7H)-one 511.3 CHIRALPAK IA 101A

4-amino-5-methyl-2-(8-(4,4,4- trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6- yl)-5-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)-5H- pyrrolo[2,3-d]pyrimidin- 6(7H)-one (fasteluting) 529.3 CHIRALPAK IA 102A

4-amino-2-(8-butyl- [1,2,4]triazolo[1,5-a]pyrazin-6- yl)-5-methyl-5-(5-(trifluoromethyl)-1,3,4- oxadiazol-2-yl)-5H- pyrrolo[2,3-d]pyrimidin-6(7H)-one (fast eluting) 475.2 CHIRALPAK IA 103A

4-amino-5-(5-cyclopropyl- 1,3,4-oxadiazol-2-yl)-5- methyl-2-(2-methyl-8-(3,3,4,4,4-pentafluorobutyl)- [1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3- d]pyrimidin-6(7H)-one (fast eluting) 551.0 CHIRALPAKIA 104a

4-amino-5-cyclopropyl-5-(5- cyclopropyl-1,3,4-oxadiazol-2-yl)-2-(8-(4,4,4-trifluorobutyl)- [1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d] pyrimidin-6(7H)-one (fast eluting) 527.4 CHIRALPAKIA 105a

4-amino-2-(8-butyl- [1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-cyclopropyl-5-(5- (trifluoromethyl)-1,3,4- oxadiazol-2-yl)-5H-pyrrolo[2,3-d]pyrimidin- 6(7H)-one (fast eluting) 501.2 CHIRALPAK IA106a

4-amino-5-cyclopropyl-2-(8- (4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6- yl)-5-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)-5H- pyrrolo[2,3-d]pyrimidin- 6(7H)-one (fasteluting) 555.1 CHIRALPAK IA 107a

4-amino-5-cyclopropyl-5-(5- cyclopropyl-1,3,4-oxadiazol-2-yl)-2-(8-(3,3,4,4,4- pentafluorobutyl)- [1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3- d]pyrimidin-6(7H)-one (fast eluting) 563.3 CHIRALPAKIA 108a

4-amino-5-cyclopropyl-5-(5- (1-fluorocyclopropyl)-1,3,4-oxadiazol-2-yl)-2-(8-(4,4,4- trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6- yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (fast eluting) 545.2 CHIRALPAK IB 109a

4-amino-5-(5-(1- fluorocyclopropyl)-1,3,4-oxadiazol-2-yl)-5-methyl-2-(8- (4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5a]pyrazin-6- yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (fast eluting) 519.2 CHIRALPAK IB

EXAMPLE 110A4-Amino-5-(5-hydroxypyridin-2-yl)-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5,7-dihydro-6H-pyrrolo [2,3-d]pyrimidin-6-one

-   Step    A—4-Amino-5-(5-methoxypyridin-2-yl)-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one:    Into a vial was placed I-A2 (100 mg, 0.324 mmol), I-10A (98 mg,    0.357 mmol), potassium bicarbonate (39.0 mg, 0.389 mmol) and t-BuOH    (8 mL). The resulting mixture was warmed at 70° C. for 16 h. The    reaction was cooled to RT and quenched by the addition of brine. The    resulting solution was extracted with EtOAc (3×) and the organic    layers were combined, dried over anhydr. Na₂SO₄, filtered and the    filtrate was conc. in vacuo to dryness. The residue was purified by    silica gel chromatography using MeOH:DCM (10%) to afford the title    product.-   Step    B—4-Amino-5-(5-hydroxypyridin-2-yl)-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one:    Into a vial, under an inert atmosphere of nitrogen, was placed    intermediate from step A (90 mg, 0.16 mmol) and DCM (9 mL) and the    reaction mixture was cooled to 0° C. To the mixture was added    tribromoborane (0.9 mL, 9.52 mmol) dropwise at 0° C. The reaction    was then stirred 16 h at rt. The reaction mixture was cooled to 0°    C., then quenched by the addition of sat. aq. NaHCO₃. The mixture    was extracted with EtOAc (3×). The organic layer was washed with    brine, dried over anhydr. Na₂SO₄, and filtered. The filtrate was    conc. in vacuo to dryness. The residue was purified by silica gel    column chromatography with MeOH:DCM (1-6%) to afford the title    compound. ¹H NMR (300 MHz, CD₃OD) δ 9.63 (s, 1H), 8.63 (s, 1H), 8.15    (d, J=2.4 Hz, 1H), 7.32 (d, J=8.7 Hz, 1H), 7.20 (dd, J=2.4, 8.7 Hz,    1H), 3.68-3.62 (m, 2H), 3.07-2.89 (m, 2H), 1.86 (s, 3H); m/z=522.1    [M+1]⁺.

Using essentially the same procedures described in Example 110A, thefollowing compounds in Table 8 were prepared.

TABLE 8 Chiral MS starting Ex. Structure Name (M + 1) material 111A

4-amino-5-(5-hydroxypyridin-2- yl)-5-methyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5- a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 486.4 Ex-40A 112A

4-amino-5-cyclopropyl-5-(5- hydroxypyridin-2-yl)-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5- a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 512.2 Ex-39A 113B

(S)-4-amino-5-(4-fluorophenyl)- 2-(8-(3-hydroxybenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6- yl)-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 483.1 Ex-86B

EXAMPLE 114A4-amino-5-cyclopropyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(pyridin-2-yl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one

Into a 40-mL vial were placed4-amino-5-(5-chloropyridin-2-yl)-5-cyclopropyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-c]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one(130 mg, 0.23 mmol), Pd/C (130 mg, 10%), ammonium formate (56 mg, 0.88mmol) and MeOH (13 mL). The resulting solution was stirred 1 h at 60° C.then cooled to RT and filtered. The filtrate was conc. in vacuo todryness. The residue was purified by silica gel column chromatographywith MeOH:DCM (10%) to afford the title compound. ¹H NMR (400 MHz,CD₃OD) δ 9.65 (s, 1H), 8.65 (s, 1H), 8.62-8.56 (m, 1H), 7.93-7.82 (m,2H), 7.40-7.37 (m, 1H), 3.66 (t, J=8.0 Hz, 2H), 3.05-2.92 (m, 2H),2.01-1.94 (m, 1H), 0.73-052 (m, 4H); m/z=532.1 [M+1]⁺.

Using essentially the same procedures described in Example 114A, thefollowing compounds in Table 9 were prepared.

TABLE 9 Chiral MS starting Ex. Structure Name (M + 1) material 115A

4-amino-5-cyclopropyl-5- (pyridin-2-yl)-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5- a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 496.0 Ex-27A 116A

4-amino-2-(8-butyl- [1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-cyclopropyl-5-(pyridin-2- yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 442.3 EX-68A

EXAMPLE 117A6-(4-Amino-5-cyclopropyl-6-oxo-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)nicotinonitrile

Into a microwave vial, under an inert atmosphere of nitrogen, was placed4-amino-5-(5-chloropyridin-2-yl)-5-cyclopropyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-c]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one(120 mg, 0.23 mmol), water (50 μL), zinc cyanide (85 mg, 0.72 mmol),tris(dibenzylideneacetone)dipalladium(0)-chloroform (85 mg, 0.093 mmol),dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (85 mg, 0.21 mmol)and DMF (5 mL). The reaction mixture was then heated to 150° C. for 40min in a microwave reactor. The reaction mixture was cooled to RT,quenched by the addition of brine. The mixture was extracted with EtOAc(3×). The organic layer was washed with brine, dried over anhydr.Na₂SO₄, and filtered. The filtrate was conc. in vacuo to dryness. Theresidue was purified by silica gel column chromatography withEtOAc:petroleum ether (30-100%). The reaction mixture was filtered andpurified by reverse phase HPLC acetonitrile:water (with 0.05% ammoniumbicarbonate modifier) to afford the title compound. ¹H NMR (300 MHz,CD₃OD) δ 9.58 (s, 1H), 8.88 (dd, J=0.9, 2.1 Hz, 1H), 8.60 (s, 1H), 8.22(dd, J=2.1, 8.4 Hz, 1H), 7.98 (dd, J=0.9, 8.4 Hz, 1H), 3.38 (t, J=7.5Hz, 2H), 2.37-2.16 (m, 4H), 1.98-1.89 (m, 1H), 0.71-0.51 (m, 4H);m/z=521.2 [M+1]⁺.

EXAMPLE 118A6-(4-Amino-5-cyclopropyl-6-oxo-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)nicotinonitrile

-   Using essentially the same procedures described in Example 117A,    Example 118A was prepared, using    4-amino-5-(5-chloropyridin-2-yl)-5-cyclopropyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one    as starting material. m/z=557.4 [M+1]⁺.

EXAMPLE 119A(S)-5-(4-fluorophenyl)-4-hydroxy-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one

-   Into a vial, under an inert atmosphere of nitrogen, was placed    Example 1A (100 mg, 0.19 mmol), tert-butyl nitrite (138 mg, 1.34    mmol), DMF (10 mL) and water (50 μL). The resulting mixture was    stirred for 30 min at 80° C., then cooled to RT and quenched by the    addition of water. The mixture was extracted with EtOAc (3×). The    organic layer was washed with brine, dried over anhydr. Na₂SO₄, and    filtered. The filtrate was conc. in vacuo to dryness. The residue    was purified by silica gel column chromatography with DCM:MeOH (10%)    to afford the title compound. ¹H NMR (500, DMSO-d₆): δ 12.73 (s,    1H). 11.37 (s, 1H), 9.51 (s, 1H), 8.93 (s, 1H), 7.46-7.43 (m, 2H),    7.20-7.16 (m, 2H), 3.57 (t, J=8.0 Hz, 2H), 3.25-3.05 (m, 2H,), 1.75    (s, 3 H), m/z=524.0 [M+1]⁺.

Using essentially the same procedures described in Example 119A, thefollowing compounds in Table 10 were prepared. The conditions employedmay utilize slight variations of reagents such as tert-butyl nitrite,isopentyl nitrite, or a combination of sodium nitrite and an acid suchas sulfuric acid in 1,2-DCE, DMA, DMF, MeCN, THF, or combinations ofsolvents thereof at elevated temperatures of 40-80° C.

TABLE 10 Chiral MS starting Ex. Structure Name (M + 1) material 120A

5-(5-chloropyridin-2-yl)-4- hydroxy-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)- [1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin- 6(7H)-one 541.1 Ex-3A 121B

5-(4-chloro-3-fluorophenyl)-4- hydroxy-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)- [1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin- 6(7H)-one 558.3 Ex-5B 122B

5-(5-fluoropyridin-2-yl)-4- hydroxy-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)- [1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin- 6(7H)-one 525.1 Ex-4B 123A

5-cyclopropyl-5-(3,4- difluorophenyl)-4-hydroxy-2-(8-(3,3,4,4,4-pentafluorobutyl)- [1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin- 6(7H)-one 568.1 Ex-6A 124B

5-cyclopropyl-5-(5- fluoropyridin-3-yl)-4-hydroxy- 2-(8-(3,3,4,4,4-pentafluorobutyl)- [1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin- 6(7H)-one 551.2 Ex-8B 125A

5-(5-fluoropyridin-3-yl)-4- hydroxy-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)- [1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin- 6(7H)-one 525.1 Ex-9A 126A

5-(4-chlorophenyl)-4-hydroxy- 5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)- [1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin- 6(7H)-one 540.0 Ex-10A 127B

4-hydroxy-5-methyl-2-(8- (3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6- yl)-5-(pyridin-2-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)- one 507.3 Ex-11B 128B

4-hydroxy-5-methyl-2-(8- (3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6- yl)-5-phenyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 506.0 Ex-12B 129B

5-(3-fluorophenyl)-4-hydroxy- 5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)- [1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5,7-dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one 524.3 Ex-14B 130B

4-hydroxy-5-methyl-5-(5- methylpyridin-2-yl)-2-(8-(3,3,3,4,4,4-pentafluorobutyl)- [1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin- 6(7H)-one 521.1 Ex-19B 131A

6-(4-hydroxy-5-methyl-6-oxo-2- (8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6- yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)nicotinonitrile 532.3 Ex-18A 132B

5-(4-chloro-3-fluorophenyl)-4- hydroxy-5-methyl-2-(2-methyl-8-(3,3,4,4,4-pentafluorobutyl)- [1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin- 6(7H)-one 572.0 Ex-90B 133B

(S)-5-(4-fluorophenyl)-4- hydroxy-5-methyl-2-(2-methyl-8-(3,3,4,4,4-pentafluorobutyl)- [1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin- 6(7H)-one 538.0 Ex-88B 134A

5-(5-chloropyridin-2-yl)-4- hydroxy-5-methyl-2-(8-(4,4,4-trifluorobutyl)- [1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin- 6(7H)-one 505.3 Ex-26A 135A

5-(4-fluoropyridin)-4-hydroxy- 5-methyl-2-(8-(4,4,4- trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6- yl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one 488.3 Ex-23A 136B

5-(5-fluoropyridin-2-yl)-4- hydroxy-5-methyl-2-(8-(4,4,4-trifluorobutyl)- [1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin- 6(7H)-one 489.1 Ex-22B 137B

4-hydroxy-5-methyl-2-(8-(4,4,4- trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6- yl)-5-(4- (trifluoromethyl)phenyl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)- one 538.3 Ex-24B 138B

5-(4-chloro-3-fluorophenyl)-4- hydroxy-5-methyl-2-(8-(4,4,4-trifluorobutyl)- [1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin- 6(7H)-one 522.2 Ex-28B 139B

5-cyclopropyl-5-(4- fluorophenyl)-4-hydroxy-2-(8-(4,4,4-trifluorobutyl)- [1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin- 6(7H)-one 514.1 Ex-30B 140B

5-(4-chlorophenyl)-5- cyclopropyl-4-hydroxy-2-(8-(4,4,4-trifluorobutyl)- [1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin- 6(7H)-one 530.5 Ex-31B 141A

5-cyclopropyl-5-(3,4- difluorophenyl)-4-hydroxy-2-(8-(4,4,4-trifluorobutyl)- [1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin- 6(7H)-one 532.0 Ex-32A 142A

5-(4-chlorophenyl)-4-hydroxy- 5-methyl-2-(8-(4,4,4- trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6- yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 504.0 Ex-29A 143B

4-hydroxy-5-methyl-5-phenyl- 2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6- yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 470.3 Ex-37B 144A

5-cyclopropyl-4-hydroxy-2-(8- (4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6- yl)-5-(4- (trifluoromethyl)phenyl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)- one 564.0 Ex-35A 145B

4-hydroxy-5-methyl-5-(pyridin- 2-yl)-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6- yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 471.1 Ex-36B 146B

5-(3,4-difluorophenyl)-4- hydroxy-5-methyl-2-(8-(4,4,4- trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6- yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 506.1 Ex-38B 147B

5-(3-chloro-4-fluorophenyl)-4- hydroxy-5-methyl-2-(8-(4,4,4-trifluorobutyl)- [1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5,7-dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one 522.3 Ex-42B 148A

4-hydroxy-5-(5- methoxypyridin-2-yl)-5-methyl-2-(8-(4,4,4-trifluorobutyl)- [1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin- 6(7H)-one 501.3 Ex-40A 149B

4-hydroxy-5-methyl-5-(5- methylpyridin-2-yl)-2-(8-(4,4,4-trifluorobutyl)- [1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin- 6(7H)-one 485.1 Ex-46B 150A

5-cyclopropyl-5-(5- fluoropyridin-2-yl)-4-hydroxy-2-(8-(4,4,4-trifluorobutyl)- [1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5,7-dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one 515.1 Ex-34A 151A

(S)-5-(4-fluorophenyl)-4- hydroxy-5-methyl-2-(8-(3,3,3-trifluoropropyl)- [1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5,7-dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one 474.1 Ex-74A 152A

5-(4-chlorophenyl)-4-hydroxy- 5-methyl-2-(8-(3,3,3- trifluoropropyl)-[1,2,4]triazolo[1,5-a]pyrazin-6- yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 490.2 Ex-76A 153B

5-(4-chloro-3-fluorophenyl)-4- hydroxy-5-methyl-2-(8-(3,3,3-trifluoropropyl)- [1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin- 6(7H)-one 508.0 Ex-75B 154A

(S)-2-(8-butyl- [1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(4-fluorophenyl)-4- hydroxy-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6- one 434.2 Ex-60A 155B

2-(8-butyl-[1,2,4]triazolo[1,5- a]pyrazin-6-yl)-5-(5-fluoropyridin-2-yl)-4-hydroxy- 5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 435.1 Ex-61B 156B

2-(8-butyl-[1,2,4]triazolo[1,5- a]pyrazin-6-yl)-5-(4-chloro-3-fluorophenyl)-4-hydroxy-5- methyl-5H-pyrrolo[2,3-d] pyrimidin-6(7H)-one468.2 Ex-62B 157A

2-(8-butyl-[1,2,4]triazolo[1,5- a]pyrazin-6-yl)-5-(4-chlorophenyl)-4-hydroxy-5- methyl-5H-pyrrolo[2,3- d]pyrimidin-6(7H)-one450.2 Ex-63A 158B

2-(8-butyl-[1,2,4]triazolo[1,5- a]pyrazin-6-yl)-5-(3,4-difluorophenyl)-4-hydroxy-5- methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 452.1 Ex-64B 159B

2-(8-butyl-[1,2,4]triazolo[1,5- a]pyrazin-6-yl)-4-hydroxy-5-methyl-5-(5- (trifluoromethyl)pyridin-2-yl)- 5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 485.1 Ex-67B 160A

2-(8-butyl-[1,2,4]triazolo[1,5- a]pyrazin-6-yl)-5-(5-chloropyridin-2-yl)-4-hydroxy- 5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 451.2 Ex-69A 161B

2-(8-butyl-[1,2,4]triazolo[1,5- a]pyrazin-6-yl)-4-hydroxy-5-methyl-5-(5-methylpyridin-2- yl)-5H-pyrrolo[2,3-d]pyrimidin- 6(7H)-one431.2 Ex-71B 162B

(S)-2-(8-(4-fluorobenzyl)- [1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(4-fluorophenyl)-4- hydroxy-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)- one 486.1 Ex-85B 163A

(S)-5-(4-fluorophenyl)-4- hydroxy-2-(8-isobutyl-[1,2,4]triazolo[1,5-a]pyrazin-6- yl)-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one 434.2 Ex-73A 164A

5-(4-chlorophenyl)-4-hydroxy- 5-methyl-2-(8-propyl-[1,2,4]triazolo[1,5-a]pyrazin-6- yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 436.1 Ex-53A 165A

(S)-5-(4-fluorophenyl)-4- hydroxy-5-methyl-2-(8-propyl-[1,2,4]triazolo[1,5-a]pyrazin-6- yl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one 420.1 Ex-52A 166B

5-(4-chloro-3-fluorophenyl)-4- hydroxy-5-methyl-2-(8-propyl-[1,2,4]triazolo[1,5-a]pyrazin-6- yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 454.1 Ex-55B 167A

5-cyclopropyl-5-(3,4- difluorophenyl)-4-hydroxy-2-(8-propyl-[1,2,4]triazolo[1,5-a] pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 464.1 Ex-58A 168A

5-(4-chlorophenyl)-4-hydroxy- 5-methyl-2-(2-methyl-8-propyl-[1,2,4]triazolo[1,5-a]pyrazin-6- yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 450.2 Ex-93A

EXAMPLE 169B5-(3,4-Difluorophenyl)-4-hydroxy-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one

-   Step    A—4-Amino-5-(3,4-difluorophenyl)-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one:    The title compound was prepared using essentially the same    procedures described in Example 1A, using intermediate I-A2 and I-5B    as starting material. m/z=541 [M+1]⁺.-   Step    B—5-(3,4-difluorophenyl)-4-hydroxy-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one:    The title compound was prepared using essentially the same    procedures described in Example 119A, using intermediate from step A    as starting material. m/z=542.0 [M+1]⁺.

EXAMPLE 170A5-(2-Fluorophenyl)-4-hydroxy-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5,7-dihydro-6H-pyrrolo [2,3-d] pyrimidin-6-one

-   Step    A—4-Amino-5-(2-fluorophenyl)-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one:    The title compound was prepared using essentially the same    procedures described in Example 1A, using intermediate I-A2 and    I-12B as starting material. m/z=523.1 [M+1]⁺.-   Step    B—5-(2-Fluorophenyl)-4-hydroxy-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one:    The title compound was prepared using essentially the same    procedures described in Example 119A, using intermediate from step A    as starting material. m/z=524.2 [M+1]⁺.

EXAMPLE 171A2-(8-Butyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(3-fluorophenyl)-4-hydroxy-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one

-   Step    A—4-amino-2-(8-butyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(3-fluorophenyl)-5-methyl-5,7-dihydro-6H-pyrrolo    [2,3-d]pyrimidin-6-one: The title compound was prepared using    essentially the same procedures described in Example 1A, using    intermediate I-A5 and I-7B as starting material. m/z=433.3 [M+1]⁺.-   Step    B—2-(8-butyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(3-fluorophenyl)-4-hydroxy-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one:    The title compound was prepared using essentially the same    procedures described in Example 119A, using intermediate from step A    as starting material. m/z=434.1 [M+1]⁺.

EXAMPLE 172A

-   (S)-5-(4-fluorophenyl)-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one

-   Into a vial, under an inert atmosphere of nitrogen, was placed    Example 1A (100 mg, 0.191 mmol), tert-butyl nitrite (138 mg, 1.340    mmol) and anhydr. DMF (10 mL) The resulting mixture was stirred for    30 min at 80° C., then cooled to RT and quenched by the addition of    water. The mixture was extracted with EtOAc (3×). The organic layer    was washed with brine, dried over anhydr. Na₂SO₄, and filtered. The    filtrate was conc. in vacuo to dryness. The residue was purified by    silica gel column chromatography with DCM:MeOH (10%) to afford    Example 119A and the title compound. ¹H NMR (300, MeOD): δ 9.75 (s,    1H), 8.68 (s, 1H), 8.57 (s, 1H), 7.49-7.44 (m, 2H), 7.16-7.10 (m,    2H), 3.70-3.65 (m, 2H), 3.11-3.93 (m, 2H,), 1.91 (s, 3 H), m/z=508.2    [M+1]⁺.

Using essentially the same procedures described in Example 172A, thefollowing compounds in Table 11 were prepared.

TABLE 11 Chiral MS starting Ex. Structure Name (M + 1) material 173A

(S)-5-(4-fluorophenyl)-2-(8- isobutyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-methyl-5,7- dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one418.2 Ex-73A 174A

(S)-5-(4-fluorophenyl)-5-methyl- 2-(8-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[1,5-a]pyrazin-6- yl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one 458.1 Ex-74A 175A

5-(5-chloropyridin-2-yl)-5- methyl-2-(8-(3,3,4,4,4- pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6- yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 525.1 Ex-3A 176B

5-(5-chloropyridin-2-yl)-5-methyl- 2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6- yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one 473.1 Ex-22B

EXAMPLE 177A5-(4-Fluorophenyl)-5-methyl-6-oxo-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide

-   Step    A—4-Bromo-5-(4-fluorophenyl)-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one:    Into a vial, under an inert atmosphere of N₂, was placed    4-Amino-5-(4-fluorophenyl)-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one    (410 mg, 0.79 mmol), tert-butyl nitrite (324 mg, 3.14 mmol),    copper(II) bromide (1227 mg, 5.49 mmol) and DCE (8 mL). The    resulting mixture was stirred at 65° C. for 1 h then cooled to RT,    diluted with EtOAc. The organic layer was washed with a 9:1 mixture    of sat. NH₄Cl:NH₄OH, dried over anhydr. Na₂SO₄, and filtered. The    filtrate was conc. in vacuo to dryness. The residue was purified by    silica gel column chromatography with EtOAc:petroleum ether (0-60%)    to afford the title compound.-   Step    B—5-(4-Fluorophenyl)-5-methyl-6-oxo-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carbonitrile:    Into a vial, under an inert atmosphere of N₂, was placed    intermediate from step A (160 mg, 0.27 mmol), copper(I) cyanide (86    mg, 0.96 mmol) and DMF (4 mL). The resulting mixture was stirred for    3 h at 150° C. then cooled to RT, diluted with EtOAc. The organic    layer was washed with a 9:1 mixture of sat. NH₄Cl:NH₄OH, dried over    anhydr. Na₂SO₄, and filtered. The filtrate was conc. in vacuo to    dryness. The residue was purified by silica gel column    chromatography with EtOAc:petroleum ether (0-0%) to afford the title    compound.-   Step    C—5-(4-Fluorophenyl)-5-methyl-6-oxo-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide:    Into a vial was placed intermediate from step B (35 mg, 0.066 mmol)    and HCl (4 mL, 12 N). The resulting mixture was stirred for 1 h at    40° C. then cooled to 0° C. and quenched by the addition of water    and EtOAc. The pH value was adjusted to pH 8 with sat. NaHCO₃. The    mixture was extracted with EtOAc (3×). The organic layer was washed    with brine, dried over anhydr. Na₂SO₄, and filtered. The filtrate    was conc. in vacuo to dryness. The residue was purified by silica    gel column chromatography with EtOAc:petroleum ether (0-80%) to    afford the title compound. ¹H NMR (300 MHz, CD₃OD) δ 9.99 (s, 1H),    8.67 (s, 1H), 7.23-7.18 (m, 2H), 6.98 (dd, J=8.7, 8.7 Hz, 2H),    3.69-3.64 (m, 2H), 3.05-2.87 (m, 2H), 2.04 (s, 3H); m/z=551.0    [M+1]⁺.

Using essentially the same procedures described in Example 177A, thefollowing compounds in Table 12 were prepared.

TABLE 12 Chiral MS starting Ex. Structure Name (M + 1) material 178A

5-cyclopropyl-6-oxo-2-(8- (3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6- yl)-5-(5-(trifluoromethyl)pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[2,3- d]pyrimidine-4-carboxamide 592.1 Ex-2A179B

5-methyl-6-oxo-2-(8-(4,4,4- trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(5- (trifluoromethyl)pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[2,3-d] pyrimidine-4-carboxamide 566.1 Ex-25B

EXAMPLE 180A

4-amino-5-cyclopropyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one

The title compound was prepared using essentially the same proceduresdescribed in Example 1A, using intermediate I-A1 and 1-44 as startingmaterial. The racemic material was resolved using chiral SFC (IB column)to afford isomers Ex-180A (faster eluting) and Ex-180B (slower eluting)of the title compound m/z=531.4[M+1]⁺

EXAMPLE 181A

4-hydroxy-5-(5-(difluoromethyl)pyridin-2-yl)-5-methyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one

The title compound was prepared using essentially the same proceduresdescribed in Example 119A, using Ex-43B as starting material. m/z=521.2[M+1]⁺.

Pharmacokinetic Profile in Rats

The triazolo-pyrazinyl compounds of Formula I have longer PK T_(1/2)(hr) in rats than the corresponding imidazo-pyrazinyl analogs

Certain imidazo-pyrazinyl analogs are disclosed in InternationalApplication No. PCT/US2015/33084, filed May 29, 2015.

-   Table 13 provides the pharmacokinetic profiles for rats for a    representative set of compounds. The results were obtained using the    following the procedure:

IV Cassette PK Assay:

Adult male Wistar-Han rats were fasted overnight and administered acassette IV dose of mixture of several compounds via a previouslyimplanted catheter in the femoral vein. Animals were allowed access tofood 4h post dose. Blood samples were collected into EDTA-containingtubes at the following time points: 0.03, 0.13, 0.25, 0.5, 1, 2, 4, 8 hpost-dose. Blood samples were stored on ice until plasma was harvestedby centrifugation. Plasma was transferred to a 96-well plate and storedat −20° C. until analysis. Concentrations of each compound in rat plasmawere determined by LC-MS/MS following protein precipitation.

TABLE 13 Compounds of Formula I Imidazo-Pyrazinyl Analogs Cassette PKImidazo-Pyrazinyl Cassette PK Ex. T_(1/2) (hr) Analog T_(1/2) (hr)  1A3.35

1.04  4B 2.97

1.41 44B 3.94

2.12

Cell-based sGC Functional Assay (CASA Assay)

Rationale

sGC is a heme-containing enzyme that converts GTP to secondary messengercGMP. Increases in cGMP levels affect several physiological processesincluding vasorelaxation through multiple downstream pathways. The rateby which sGC catalyzes cGMP formation is greatly increased by NO and byrecently discovered NO-independent activators and stimulators.Heme-dependent activators (HDAs) preferentially activate sGC containinga ferrous heme group. To determine the effect of sGC activators onenzyme activity, the CASA assay was developed to monitor the generationof cGMP in a cell line that stably expresses the heterodimeric sGCprotein.

Methods

-   A CHO-K1 cell line stably expressing the sGC α1/β1 heterodimer was    generated using a standard transfection protocol. CHO-K1 cells were    transfected with plasmids pIREShyghsGCα1 and pIRESneo-hsGCβ1    simultaneously using FUGENE reagent. Clones that stably express both    subunits were selected with hygromycin and neomycin for ˜2 weeks.    Clone #7 was chosen for the assay and was designated CHO-K1/sGC.    CHO-K1/sGC cells were maintained in F-K12 medium containing 10%    heat-inactivated Fetal Bovine Serum (FBS), 100 μg/mL    penicillin/streptomycin, 0.5 mg/mL hygromycin and 0.25 mg/mL G418.    The cells were then cryopreserved in LN2. On the day of the assay,    cells thawed and resuspended in EBSS Assay Buffer (Sigma, E3024)    supplemented with 5 mM MgCl₂, 10 mM HEPES    (4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid) and 0.05% BSA    (bovine serum albumin) (EAB) and cell density was then adjusted to    4×105/mL with EAB, IBMX (3-isobutyl-1-methylxanthin, 0.5 mM) was    added to inhibit degradation of cGMP. Compounds were diluted from    DMSO stock solutions and added to the assay at a final DMSO    concentration of 2.5%. Cells were incubated with compounds in the    presence and absence of 1 μM of Diethylenetriamine/nitric oxide    adduct (DETA-NO; Sigma, 17018) for 1 hr at 37° C. At the end of the    incubation period, the reaction was terminated and the cells were    lysed with the detection reagents from Cisbio Kits. The level of    intracellular cGMP was determined using an HTRF-based assay kit    (CisBio, 62GM2PEC), which detects the displacement of a fluorescence    labeled cGMP from its specific antibody. The cGMP produced by test    compounds was directly compared to the maximum cGMP production (this    value was set to equal 100% activation.) of the published sGC-HDA    Compound A:

-   (Example 1 in WO 2010/065275, published Jun. 10, 2010). The test    compounds' activities were then expressed as a percentage of    Compound A, the standard in every experiment. This percent    activation was calculated either in the presence or absence of    DETA-NO which was then plotted. IP and maximum fold induction was    derived using ADA analysis software for 4P fit.

The compounds in the Examples of the instant invention had inflectionpoints (IP) less than or equal to 10 μM and more particularly less thanor equal to about 1 μM. Most preferred compounds had an IP of less thanor equal to about 500 nM. Data for the compounds of the Examples isprovided in Table 14.

TABLE 14 Ex. IP (nM) % Act. 1A 186.5 196 2A 127.8 111 3A 40.4 161 4B117.5 157 5B 20.9 147 6A 27.0 140 7A 41.4 185 8B 294.5 177 9A 63.0 11910A 15.8 137 11B 25.2 208 12B 11.1 122 13B 80.6 109 14B 5.5 90 15A 315.7139 16B 13.1 77 17B 36.1 119 18A 38.6 75 19B 14.7 71 20A 176.1 131 21B43.1 99 22B 38.3 130 23A 29.6 163 24B 27.1 133 25B 27.0 131 26A 27.8 16227A 277.6 178 28B 20.0 171 29A 11.4 101 30B 36.7 117 31B 13.0 104 32A77.4 144 33A 5.6 107 34A 427.9 235 35A 416.3 164 36B 56.5 82 37B 11.5112 38A 11.0 120 39A 20.1 96 40A 98.9 130 41A 27.8 151 42B 8.7 82 43B45.6 69 44B 110.9 120 45B 44.2 156 46B 10.1 67 47B 143.7 114 48A 77.9 8549B 595.1 127 50B 150.2 191 51B 15.1 144 52A 63.2 96 53A 26.9 122 54B318.2 210 55B 45.6 99 56A 384.0 81 57A 576.8 119 58A 242.0 169 59A 263.0119 60A 22.6 121 61B 9.7 177 62B 51.0 267 63A 21.9 187 64B 5.1 90 65A2.6 104 66A 34.2 162 67B 25.5 119 68A 18.7 113 69A 13.7 158 70A 41.8 13371B 5.5 118 72B 28.5 82 73A 44.1 101 74A 55.6 110 75B 20.0 136 76A 153.6120 77B 332.8 112 78B 550.4 83 79A 324.6 152 80A 2488.0 115 81B 698.4115 82A 555.4 125 83A 269.7 100 84B 55.7 101 85B 10.6 106 86B 26.4 12687B 80.2 138 88B 65.0 137 89B 260.2 109 90B 36.6 135 91A 668.1 105 92B4828.0 167 93A 439.0 159 94A 79.4 138 95B 256.7 74 96B 134.3 108 97B219.5 106 98B 86.1 164 99A 47.5 113 100A 127.4 184 101A 120.6 154 102A29.1 132 103A 218.6 104 104A 257.9 117 105A 26.7 176 106A 15.5 95 107A74.7 76 108A 14.7 107 109A 7.3 92 110A 138.9 70 111A 369.5 75 112A 212.591 113B 762.9 171 114A 143.6 122 115A 232.7 118 116A 19.7 85 117A 49.2140 118A 84.1 72 119A 133.7 124 120A 155.3 107 121B 130.4 222 122B 140.6100 123A 203.6 78 124B 1051.0 88 125A 575.1 87 126A 131.9 102 127B1255.0 129 128B 127.9 106 129B 51.7 66 130B 503.1 109 131A 1471.0 99132B 441.9 119 133B 856.2 87 134A 856.8 134 135A 182.9 108 136B 513.9 69137B 596.7 102 138B 343.9 164 139B 672.8 169 140B 277.3 150 141A 183.5133 142A 207.2 137 143A 301.0 114 144A 1296.0 87 145B 1218.0 64 146B45.5 154 147B 213.5 94 148A 1092.0 96 149B 990.3 63 150A 1222.0 74 151A1489.0 120 152A 132.6 70 153B 310.1 104 154A 27.2 100 155B 163.0 159156B 23.3 102 157A 72.7 161 158B 102.0 232 159B 208.6 73 160A 50.2 96161B 303.0 95 162B 96.7 100 163A 1635.0 109 164A 780.0 253 165A 1518.0114 166B 711.4 117 167A 1088.0 70 168A 1454.0 77 169B 110.9 116 170A 9.5125 171A 136.9 90 172A 212.5 122 173A 574.0 176 174A 1346.0 133 175A384.1 115 176B 526.0 166 177A 127.7 168 178A 199.0 108 179B 90.2 101180B 487.5 97 181B 749.0 55

Acute Efficacy in Spontaneously Hypertensive Rats (SHR)

Spontaneously hypertensive rats (SHR, male, Charles River) wereimplanted with DSI TA11PA-C40 telemetry device (Data Sciences, Inc., St.Paul, Minn.) under isoflurane or ketamine/metomidine anesthesia. Thetelemetry unit catheter was inserted into the descending aorta via thefemoral artery and the telemetry device was implanted subcutaneously inthe left flank area. Animals were allowed to recover from surgery for 14days before the start of any studies. Blood pressure, heart rate, andactivity signals from conscious, freely moving rats were recordedcontinuously for 30 seconds every 10 minutes. On the day prior toadministration of compound, a single oral dose of vehicle (10%transcutol/20% Cremophor/70% water) was administered to all animals toestablish baseline control data. The blood pressure lowering efficacy ofcompound (PO) or vehicle was evaluated following a single oral gavage.Data were collected as hourly averages, and changes in blood pressurewere calculated by subtracting control baseline data on an hourly basis.Animals were maintained on normal diet with a 12 hour light-dark cycle.

Maximum peak decreases of systolic blood pressure (SBP) in SHR at aparticular P.O. dose (mpk milligrams per kilogram) for the followingrepresentative compounds are provided. Category A=SBP in SHRs <20 mmHg;Category B=SBP in SHRs 20-40 mmHg; Category C=SBP in SHRs >40 mmHg

TABLE 15 Dose, P.O. Ex. mpk Cat. 1A 0.3 C 2A 0.3 A 3A 0.3 B 4B 0.3 C 7A0.3 B 8B 3 B 9A 1 B 11B 0.3 B 12B 0.1 B 13B 1 B 17B 0.3 A 18A 0.3 C 20A1 C 25B 0.3 B 33A 0.3 C 34A 0.3 C 36B 1 B 39A 0.3 B 41A 0.3 B 44B 1 B56A 3 B 60A 0.3 C 61B 0.3 C 65A 0.3 C 67B 0.3 B 73A 1 B 74A 1 B 76A 0.3A 77B 1 A 78B 3 B 79A 1 B 85B 0.3 C 88B 1 C 94A 1 C 95B 0.3 C 98B 1 B103A 2 A 104A 3 C 105A 0.3 B 106A 0.3 C 107A 3 C 110A 3 B 112A 3 A 114A1 B 115A 1 B 119A 1 B 120A 1 B 121B 1 B 122B 1 B 125A 3 A 132B 1 A 134A1 B 135A 1 B 136B 3 B 138B 1 C 140B 1 A 141A 1 B 142A 0.3 B 143A 1 B146B 0.3 B 151A 3 B 152A 3 B 154A 0.3 B 155B 1 B 156B 0.3 C 158B 0.3 C160A 0.3 B 164A 2 B 165A 3 B 166B 3 B 173A 1 A 177A 1 C 178A 1 B 179B0.3 B

1. A compound having structural Formula I:

or a pharmaceutically acceptable salt thereof wherein C* indicates apotential chiral carbon atom; R¹ is (1) hydrogen (2) (C₁₋₆)alkyl, (3)halo(C₁₋₆)alkyl, (4) (C₁₋₆)alkyl-O—, (5) halo(C₁₋₆)alkyl-O—, (6)(C₁₋₆)alkyl-NH—, (7) halo(C₁₋₆)alkyl-NH—, (8)—(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl, (9) —(C₁₋₃)alkyl-aryl, wherein aryl isunsubstituted or substituted by one, two, or three R⁷, (10) arylunsubstituted or substituted by one, two, or three R⁷, (11)(C₃₋₇)cycloalkyl, or (12) —(C₁₋₃)alkyl-heteroaryl wherein the heteroarylis a 5- or 6-membered ring containing one, two, or three heteroatomsindependently selected from the group consisting of N, O, and S, andwherein heteroaryl is unsubstituted or substituted by one, two, or threeR⁷; R² is (1) (C₁₋₃)alkyl, or (2) (C₃₋₇)cycloalkyl; R³ is (1) arylunsubstituted or substituted by one, two, or three R⁶, (2) five- orsix-membered heteroaryl containing one, two, or three heteroatomsindependently selected from N, O and S, wherein heteroaryl isunsubstituted or substituted by one, two, or three R⁶, (3) (C₁₋₃)alkyl,or (4) (C₃₋₇)cycloalkyl; R⁴ is (1) hydrogen, (2) (C₁₋₃)alkyl, (3)halo(C₁₋₃)alkyl, or (4) (C₃₋₇)cycloalkyl; R⁵ is (1) hydrogen, (2)hydroxy, (3) —N(R^(8a))(R^(8b)), (4) —COOH, (5) —C(O)NH₂, (6)(C₁₋₃)alkyl, (7) (C₃₋₇)cycloalkyl, or (8) four- to six-memberedmonocyclic heterocyclyl containing 1 N heteroatom, wherein theheterocyclyl is unsubstituted or substituted by one to two R⁹; each R⁶is independently (1) (C₁₋₃)alkyl, (2) halo(C₁₋₃)alkyl, (3) (C₁₋₃)alkoxy,(4) halo(C₁₋₃)alkoxy, (5) (C₃₋₇)cycloalkyl, unsubstituted or substitutedby halo, (6) halo, (7) cyano, (8) hydroxy, (9) —NH₂, (10)—(C₁₋₃)alkyl—COOH, or (11) —(C₁₋₃)alkyl-COO(C₁₋₄)alkyl; each R⁷ isindependently (1) (C₁₋₃)alkoxy, (2) halo, (3) hydroxy, or (4)(C₁₋₃)alkyl; R^(8a) and R^(8b) are independently (1) hydrogen, (2)(C₁₋₃)alkyl, or (3) (C₃₋₇)cycloalkyl; and R⁹ is (1) (C₁₋₃)alkyl, (2)halo(C₁₋₃)alkyl, or (3) hydroxy.
 2. A compound having structural FormulaI:

or a pharmaceutically acceptable salt thereof wherein C* indicates apotential chiral carbon atom; R¹ is (1) hydrogen (2) (C₁₋₆)alkyl, (3)halo(C₁₋₆)alkyl, (4) (C₁₋₆)alkyl-O—, (5) halo(C₁₋₆)alkyl-O—, (6)(C₁₋₆)alkyl-NH—, (7) halo(C₁₋₆)alkyl-NH—, (8)—(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl, (9) —(C₁₋₃)alkyl-aryl, wherein aryl isunsubstituted or substituted by one, two, or three R⁷, (10) arylunsubstituted or substituted by one, two, or three R⁷, (11)(C₃₋₇)cycloalkyl, or (12) —(C₁₋₃)alkyl-heteroaryl wherein the heteroarylis a 5- or 6-membered ring containing one, two, or three heteroatomsindependently selected from the group consisting of N, O, and S, andwherein heteroaryl is unsubstituted or substituted by one, two, or threeR⁷; R² is (1) (C₁₋₃)alkyl, or (2) (C₃₋₇)cycloalkyl; R³ is (1) arylunsubstituted or substituted by one, two, or three R⁶, or (2) five- orsix-membered heteroaryl containing one, two, or three heteroatomsindependently selected from N, O and S, wherein heteroaryl isunsubstituted or substituted by one, two, or three R⁶; R⁴ is (1)hydrogen, (2) (C₁₋₃)alkyl, (3) halo(C₁₋₃)alkyl, or (4) (C₃₋₇)cycloalkyl;R⁵ is (1) hydrogen, (2) hydroxy, (3) —N(R^(8a))(R^(8b)), (4) —COOH, (5)—C(O)NH₂, (6) (C₁₋₃)alkyl, (7) (C₃₋₇)cycloalkyl, or (8) four- tosix-membered monocyclic heterocyclyl containing 1 N heteroatom, whereinthe heterocyclyl is unsubstituted or substituted by one to two R⁹; eachR⁶ is independently (1) (C₁₋₃)alkyl, (2) halo(C₁₋₃)alkyl, (3)(C₁₋₃)alkoxy, (4) halo(C₁₋₃)alkoxy, (5) (C₃₋₇)cycloalkyl, unsubstitutedor substituted by halo, (6) halo, (7) cyano, (8) hydroxy, (9) —NH₂, (10)—(C₁₋₃)alkyl—COOH, or (11) —(C₁₋₃)alkyl-COO(C₁₋₄)alkyl; each R⁷ isindependently (1) (C₁₋₃)alkoxy, (2) halo, (3) hydroxy, or (4)(C₁₋₃)alkyl; R^(8a) and R^(8b) are independently (1) hydrogen, (2)(C₁₋₃)alkyl, or (3) (C₃₋₇)cycloalkyl; and R⁹ is (1) (C₁₋₃)alkyl, (2)halo(C₁₋₃)alkyl, or (3) hydroxy.
 3. The compound of claim 1 or apharmaceutically acceptable salt thereof wherein: R³ is arylunsubstituted or substituted by one, two, or three R⁶.
 4. The compoundof claim 1 or a pharmaceutically acceptable salt thereof wherein: R⁵ is—N(R^(8a))(R^(8b)).
 5. The compound of claim 1 or a pharmaceuticallyacceptable salt thereof wherein: R¹ is (C₁₋₆)alkyl, halo(C₁₋₆)alkyl,—(C₁₋₃)alkyl-aryl, wherein aryl is unsubstituted or substituted by one,two, or three R⁷.
 6. The compound of claim 1 or a pharmaceuticallyacceptable salt thereof wherein R⁵ is hydroxy.
 7. The compound of claim6 or a pharmaceutically acceptable salt thereof wherein: R¹ is(C₁₋₆)alkyl, halo(C₁₋₆)alkyl, or —(C₁₋₃)alkyl-aryl, wherein aryl isunsubstituted or substituted by one, two, or three R⁷.
 8. The compoundof claim 1 or a pharmaceutically acceptable salt thereof wherein R³ isfive- or six-membered heteroaryl containing one, two, or threeheteroatoms independently selected from the group consisting of N, O andS, wherein heteroaryl is unsubstituted or substituted by one, two, orthree R⁶.
 9. The compound of claim 8 or a pharmaceutically acceptablesalt thereof wherein: R⁵ is —N(R^(8a))(R^(8b)).
 10. The compound ofclaim 9 or a pharmaceutically acceptable salt thereof wherein: R¹ is(C₁₋₆)alkyl, halo(C₁₋₆)alkyl, or —(C₁₋₃)alkyl-aryl, wherein aryl isunsubstituted or substituted by one, two, or three R⁷.
 11. The compoundof claim 8 or a pharmaceutically acceptable salt thereof wherein R⁵ ishydroxy.
 12. The compound of claim 11 or a pharmaceutically acceptablesalt thereof wherein: R¹ is (C₁₋₆)alkyl, halo(C₁₋₆)alkyl, or—(C₁₋₃)alkyl-aryl, wherein aryl is unsubstituted or substituted by one,two, or three R⁷.
 13. The compound of claim 1, which is:4-amino-5-(4-fluorophenyl)-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-c]pyrimidin-6(7H)-one,4-amino-5-cyclopropyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(5-(trifluoromethyl)pyridin-2-yl)-5H-pyrrolo[2,3-c]pyrimidin-6(7H)-one,4-amino-5-(5-chloropyridin-2-yl)-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-c]pyrimidin-6(7H)-one,4-amino-5-(5-fluoropyridin-2-yl)-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-c]pyrimidin-6(7H)-one,4-amino-5-(4-chloro-3-fluorophenyl)-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-c]pyrimidin-6(7H)-one,4-amino-5-cyclopropyl-5-(3,4-difluorophenyl)-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-c]pyrimidin-6(7H)-one,4-amino-5-(5-chloropyridin-2-yl)-5-cyclopropyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-c]pyrimidin-6(7H)-one,4-amino-5-cyclopropyl-5-(5-fluoropyridin-3-yl)-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(5-fluoropyridin-3-yl)-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(4-chlorophenyl)-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-c]pyrimidin-6(7H)-one,4-amino-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(pyridin-2-yl)-5H-pyrrolo[2,3-c]pyrimidin-6(7H)-one,(12)4-amino-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-phenyl-5H-pyrrolo[2,3-c]pyrimidin-6(7H)-one,4-amino-5-(6-cyclopropylpyridin-3-yl)-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-c]pyrimidin-6(7H)-one,4-amino-5-(3-fluorophenyl)-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-c]pyrimidin-6(7H)-one,4-amino-5-cyclopropyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(5-(trifluoromethyl)pyridin-2-yl)-5H-pyrrolo[2,3-c]pyrimidin-6(7H)-one,4-amino-5-(6-(1,1-difluoroethyl)pyridin-3-yl)-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-c]pyrimidin-6(7H)-one,4-amino-5-cyclopropyl-5-(5-methylpyridin-2-yl)-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,6-(4-amino-5-methyl-6-oxo-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)nicotinonitrile,4-amino-5-methyl-5-(5-methylpyridin-2-yl)-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(1-isopropyl-1H-1,2,3-triazol-4-yl)-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-cyclopropyl-5-(5-methylpyrazin-2-yl)-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(5-fluoropyridin-2-yl)-5-methyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(4-fluorophenyl)-5-methyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-methyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(4-(trifluoromethyl)phenyl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-methyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(5-(trifluoromethyl)pyridin-2-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(5-chloropyridin-2-yl)-5-methyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(5-chloropyridin-2-yl)-5-cyclopropyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(4-chloro-3-fluorophenyl)-5-methyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(4-chlorophenyl)-5-methyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-cyclopropyl-5-(4-fluorophenyl)-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(4-chlorophenyl)-5-cyclopropyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-cyclopropyl-5-(3,4-difluorophenyl)-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(4-chloro-3-fluorophenyl)-5-cyclopropyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-cyclopropyl-5-(5-fluoropyridin-2-yl)-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-cyclopropyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(4-(trifluoromethyl)phenyl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-methyl-5-(pyridin-2-yl)-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-methyl-5-phenyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(3,4-difluorophenyl)-5-methyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-cyclopropyl-5-(5-methoxypyridin-2-yl)-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(5-methoxypyridin-2-yl)-5-methyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(5-chloropyrimidin-2-yl)-5-cyclopropyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(3-chloro-4-fluorophenyl)-5-methyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(5-(difluoromethyl)pyridin-2-yl)-5-methyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-cyclopropyl-5-(5-(difluoromethyl)pyridin-2-yl)-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(6-(1,1-difluoroethyl)pyridin-3-yl)-5-methyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-methyl-5-(5-methylpyridin-2-yl)-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-cyclopropyl-5-(5-methylpyridin-2-yl)-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,6-(4-amino-5-methyl-6-oxo-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)nicotinonitrile,4-amino-5-methyl-5-(6-methyl-5-(trifluoromethyl)pyridin-2-yl)-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-methyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(5-(trifluoromethyl)pyrazin-2-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-methyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(4-fluorophenyl)-5-methyl-2-(8-propyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(4-chlorophenyl)-5-methyl-2-(8-propyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(5-fluoropyridin-2-yl)-5-methyl-2-(8-propyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,5-(5-fluoropyridin-2-yl)-4-hydroxy-5-methyl-2-(8-propyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-cyclopropyl-2-(8-propyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(5-(trifluoromethyl)pyridin-2-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(5-chloropyridin-2-yl)-5-cyclopropyl-2-(8-propyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-cyclopropyl-5-(3,4-difluorophenyl)-2-(8-propyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-cyclopropyl-5-(5-fluoropyridin-2-yl)-2-(8-propyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-2-(8-butyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(4-fluorophenyl)-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-2-(8-butyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(5-fluoropyridin-2-yl)-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-2-(8-butyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(4-chloro-3-fluorophenyl)-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-2-(8-butyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(4-chlorophenyl)-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-2-(8-butyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(3,4-difluorophenyl)-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-2-(8-butyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-cyclopropyl-5-(3,4-difluorophenyl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-2-(8-butyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-cyclopropyl-5-(5-fluoropyridin-2-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-2-(8-butyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-methyl-5-(5-(trifluoromethyl)pyridin-2-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-2-(8-butyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(5-chloropyridin-2-yl)-5-cyclopropyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-2-(8-butyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(5-chloropyridin-2-yl)-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-2-(8-butyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-cyclopropyl-5-(5-(trifluoromethyl)pyridin-2-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-2-(8-butyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-methyl-5-(5-methylpyridin-2-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-2-(8-butyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-cyclopropyl-5-(5-methylpyridin-2-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(4-fluorophenyl)-2-(8-isobutyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(4-fluorophenyl)-5-methyl-2-(8-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(4-chloro-3-fluorophenyl)-5-methyl-2-(8-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(4-chlorophenyl)-5-methyl-2-(8-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-methyl-5-(4-(trifluoromethyl)phenyl)-2-(8-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-methyl-5-(5-(trifluoromethyl)pyridin-2-yl)-2-(8-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(5-chloropyridin-2-yl)-5-methyl-2-(8-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-cyclopropyl-5-(5-(trifluoromethyl)pyridin-2-yl)-2-(8-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(5-fluoropyridin-2-yl)-5-methyl-2-(8-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(5-chloropyridin-2-yl)-5-cyclopropyl-2-(8-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-cyclopropyl-5-(3,4-difluorophenyl)-2-(8-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(3,4-difluorophenyl)-5-methyl-2-(8-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-2-(8-(4-fluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(4-fluorophenyl)-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(4-fluorophenyl)-2-(8-(3-methoxybenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-2-(8-(4-fluorobenzyl)-2-methyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(4-fluorophenyl)-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(4-fluorophenyl)-5-methyl-2-(2-methyl-8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(5-fluoropyridin-2-yl)-5-methyl-2-(2-methyl-8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(4-chloro-3-fluorophenyl)-5-methyl-2-(2-methyl-8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(4-fluorophenyl)-5-methyl-2-(2-methyl-8-propyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(5-fluoropyridin-2-yl)-5-methyl-2-(2-methyl-8-propyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(4-chlorophenyl)-5-methyl-2-(2-methyl-8-propyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,2-([1,2,4]triazolo[1,5-a]pyrazin-6-yl)-4-amino-5-(4-chlorophenyl)-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(1-cyclopropyl-1H-1,2,3-triazol-4-yl)-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-cyclopropyl-5-(1-cyclopropyl-1H-1,2,3-triazol-4-yl)-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-Amino-5-methyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-5-methyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-5-methyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-methyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-2-(8-butyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-methyl-5-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-5-methyl-2-(2-methyl-8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-cyclopropyl-5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-2-(8-butyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-cyclopropyl-5-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-cyclopropyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-cyclopropyl-5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-cyclopropyl-5-(5-(1-fluorocyclopropyl)-1,3,4-oxadiazol-2-yl)-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(5-(1-fluorocyclopropyl)-1,3,4-oxadiazol-2-yl)-5-methyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(5-hydroxypyridin-2-yl)-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-5-(5-hydroxypyridin-2-yl)-5-methyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-cyclopropyl-5-(5-hydroxypyridin-2-yl)-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-(4-fluorophenyl)-2-(8-(3-hydroxybenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-5-cyclopropyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(pyridin-2-yl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-amino-5-cyclopropyl-5-(pyridin-2-yl)-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-amino-2-(8-butyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-cyclopropyl-5-(pyridin-2-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,6-(4-amino-5-cyclopropyl-6-oxo-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)nicotinonitrile,6-(4-amino-5-cyclopropyl-6-oxo-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)nicotinonitrile,5-(4-Fluorophenyl)-4-hydroxy-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,5-(5-chloropyridin-2-yl)-4-hydroxy-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,5-(4-chloro-3-fluorophenyl)-4-hydroxy-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,5-(5-fluoropyridin-2-yl)-4-hydroxy-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,5-cyclopropyl-5-(3,4-difluorophenyl)-4-hydroxy-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,5-cyclopropyl-5-(5-fluoropyridin-3-yl)-4-hydroxy-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,5-(5-fluoropyridin-3-yl)-4-hydroxy-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,5-(4-chlorophenyl)-4-hydroxy-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-hydroxy-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(pyridin-2-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-hydroxy-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-phenyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,5-(3-fluorophenyl)-4-hydroxy-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,4-hydroxy-5-methyl-5-(5-methylpyridin-2-yl)-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,6-(4-hydroxy-5-methyl-6-oxo-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)nicotinonitrile,5-(4-chloro-3-fluorophenyl)-4-hydroxy-5-methyl-2-(2-methyl-8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,5-(4-fluorophenyl)-4-hydroxy-5-methyl-2-(2-methyl-8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,5-(5-chloropyridin-2-yl)-4-hydroxy-5-methyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,5-(4-fluorophenyl)-4-hydroxy-5-methyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,5-(5-fluoropyridin-2-yl)-4-hydroxy-5-methyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-hydroxy-5-methyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(4-(trifluoromethyl)phenyl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,5-(4-chloro-3-fluorophenyl)-4-hydroxy-5-methyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,5-cyclopropyl-5-(4-fluorophenyl)-4-hydroxy-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,5-(4-chlorophenyl)-5-cyclopropyl-4-hydroxy-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,5-cyclopropyl-5-(3,4-difluorophenyl)-4-hydroxy-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,5-(4-chlorophenyl)-4-hydroxy-5-methyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-hydroxy-5-methyl-5-phenyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,5-cyclopropyl-4-hydroxy-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(4-(trifluoromethyl)phenyl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-hydroxy-5-methyl-5-(pyridin-2-yl)-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,5-(3,4-difluorophenyl)-4-hydroxy-5-methyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,5-(3-chloro-4-fluorophenyl)-4-hydroxy-5-methyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one4-hydroxy-5-(5-methoxypyridin-2-yl)-5-methyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,4-hydroxy-5-methyl-5-(5-methylpyridin-2-yl)-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,5-cyclopropyl-5-(5-fluoropyridin-2-yl)-4-hydroxy-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,5-(4-fluorophenyl)-4-hydroxy-5-methyl-2-(8-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,5-(4-chlorophenyl)-4-hydroxy-5-methyl-2-(8-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,5-(4-chloro-3-fluorophenyl)-4-hydroxy-5-methyl-2-(8-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,2-(8-butyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(4-fluorophenyl)-4-hydroxy-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,2-(8-butyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(5-fluoropyridin-2-yl)-4-hydroxy-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,2-(8-butyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(4-chloro-3-fluorophenyl)-4-hydroxy-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,2-(8-butyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(4-chlorophenyl)-4-hydroxy-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,2-(8-butyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(3,4-difluorophenyl)-4-hydroxy-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,2-(8-butyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-4-hydroxy-5-methyl-5-(5-(trifluoromethyl)pyridin-2-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,2-(8-butyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(5-chloropyridin-2-yl)-4-hydroxy-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,2-(8-butyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-4-hydroxy-5-methyl-5-(5-methylpyridin-2-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,2-(8-(4-fluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(4-fluorophenyl)-4-hydroxy-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,5-(4-fluorophenyl)-4-hydroxy-2-(8-isobutyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,5-(4-chlorophenyl)-4-hydroxy-5-methyl-2-(8-propyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,5-(4-fluorophenyl)-4-hydroxy-5-methyl-2-(8-propyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,5-(4-chloro-3-fluorophenyl)-4-hydroxy-5-methyl-2-(8-propyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,5-cyclopropyl-5-(3,4-difluorophenyl)-4-hydroxy-2-(8-propyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,5-(4-chlorophenyl)-4-hydroxy-5-methyl-2-(2-methyl-8-propyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,5-(3,4-difluorophenyl)-4-hydroxy-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,5-(2-fluorophenyl)-4-hydroxy-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,2-(8-butyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(3-fluorophenyl)-4-hydroxy-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,5-(4-Fluorophenyl)-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,5-(4-fluorophenyl)-2-(8-isobutyl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,5-(4-fluorophenyl)-5-methyl-2-(8-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,5-(5-chloropyridin-2-yl)-5-methyl-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,5-(5-fluoropyridin-2-yl)-5-methyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one,5-(4-fluorophenyl)-5-methyl-6-oxo-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide,5-cyclopropyl-6-oxo-2-(8-(3,3,4,4,4-pentafluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(5-(trifluoromethyl)pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide,5-methyl-6-oxo-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(5-(trifluoromethyl)pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide,4-amino-5-cyclopropyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,or4-hydroxy-5-(5-(difluoromethyl)pyridin-2-yl)-5-methyl-2-(8-(4,4,4-trifluorobutyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-5H-pyrrolo[2,3-c]pyrimidin-6(7H)-one,or a pharmaceutically acceptable salt thereof.
 14. A method foractivating soluble guanylate cyclase comprising the step ofadministering an amount efficacious therefor of the compound of claim 1or a pharmaceutically acceptable salt thereof.
 15. A method for thetreatment of one or more conditions selected from cardiovasculardisease, endothelial dysfunction, diastolic dysfunction,atherosclerosis, hypertension, heart failure, pulmonary hypertension,angina pectoris, thrombosis, restenosis, myocardial infarction, stroke,cardiac insufficiency, fibrosis, pulmonary hypertonia, erectiledysfunction, asthma bronchiale, chronic kidney disease, diabetes orcirrhosis of the liver in a patient comprising administering atherapeutically effective amount of the compound of claim 1, or apharmaceutically acceptable salt thereof, to a patient in need thereof.16. A method for the treatment of hypertension comprising administeringa therapeutically effective amount of the compound of claim 1, or apharmaceutically acceptable salt thereof, to a patient in need thereof.17. A method for the treatment of heart failure comprising administeringa therapeutically effective amount of the compound of claim 1, or apharmaceutically acceptable salt thereof, to a patient in need thereof.18. A pharmaceutical composition comprised of the compound of claim 1,or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 19. The pharmaceutical composition of claim 18further comprising one or more additional active agents is selected froman angiotensin converting enzyme inhibitor, an angiotensin II receptorantagonist, a neutral endopeptidase inhibitor, an aldosteroneantagonist, a renin inhibitor, an endothelin receptor antagonist, analdosterone synthase inhibitor, a phosphodiesterase-5 inhibitor, avasodilator, a calcium channel blocker, a potassium channel activator, adiuretic, a sympatholitic, a beta-adrenergic blocking drug, an alphaadrenergic blocking drug, a central alpha adrenergic agonist, aperipheral vasodilator, a lipid lowering agent or a metabolic alteringagent. 20-24. (canceled)